TWI351400B

TWI351400B -

Info

Publication number: TWI351400B
Application number: TW094106583A
Authority: TW
Inventors: Fushimi Nobuhiko; Isaji Masayuki; Fujikura Hideki
Original assignee: Kissei Pharmaceutical
Priority date: 2004-03-04
Filing date: 2005-03-04
Publication date: 2011-11-01
Also published as: EP1721904A4; JPWO2005085237A1; EP1721904A1; CA2557269A1; JP4950657B2; WO2005085237A1; NZ549629A; BRPI0508259A; CN1934103B; KR20060129054A; TW200540166A; KR101141558B1; AU2005219779A1; ZA200608028B; CN1934103A; US20070197450A1; CA2557269C; US8058245B2; AU2005219779B2

Description

1351400 九、發明說明：【發明所屬之技術領域】本發明係關於作為醫藥品有用之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，及含有該衍生物之醫藥組成物及其醫藥用途。1351400 IX. Description of the Invention: [Technical Field] The present invention relates to a condensed heterocyclic derivative useful as a pharmaceutical or a pharmacologically acceptable salt thereof or a precursor thereof, and a pharmaceutical composition containing the same and Its medical use.

詳言之，本發明係關於作為例如糖尿病、葡萄糖耐性異常、糖尿病性併發症或肥胖症等由高血糖症所引起之疾病之預防或治療藥有用，具有人體SGLT活性抑制作用之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，及含有該衍生物之醫藥組成物及其醫藥用途。【先前技術】糖尿病為以飲食習慣之改變或運動不足為背景之生活習慣病之一。因此對糖尿病患者實行飲食療法或運動療法，但在無法充分控制或難以繼續實行的情況下，則併用藥物療法。又，由大規模臨床試驗確認，治療糖尿病以阻止慢性併發症之發病或病情進展，必須長期嚴格控制血糖 (例如，參照下述文獻1及2)。再者，有關葡萄糖耐性異常或大動脈障礙之許多流行病學研究，顯示除糖尿病外，屬於邊緣型之葡萄糖耐性異常亦為大動脈障礙之危險因子，故矯正飯後高血糖之必要性亦受注目（例如，參照下述文獻3)。目前，以近年糖尿病患者數之急劇增加為背景而研發各種藥劑作為糖尿病治療藥，而使用有雙胍藥（B i g u a n i d e )、石黃醒尿素藥（Sulfonylurea)、膜島素敏感性增強藥及a -312XP/發明說明書(補件)/94-07/94 ] 06583 1351400In particular, the present invention relates to a preventive or therapeutic drug for diseases caused by hyperglycemia such as diabetes, impaired glucose tolerance, diabetic complications, or obesity, and a condensed heterocyclic derivative having an inhibitory effect on SGLT activity of human body. Or a pharmacologically acceptable salt thereof or a prodrug thereof, and a pharmaceutical composition containing the same and its medical use. [Prior Art] Diabetes is one of life-related diseases in the context of changes in eating habits or lack of exercise. Therefore, diet therapy or exercise therapy is applied to diabetic patients, but in the case where it is not adequately controlled or difficult to continue, drug therapy is used in combination. Further, it has been confirmed by large-scale clinical trials that treatment of diabetes to prevent the onset of chronic complications or progression of the disease requires strict control of blood glucose for a long period of time (for example, refer to the following documents 1 and 2). Furthermore, many epidemiological studies on impaired glucose tolerance or aortic disorders have shown that, in addition to diabetes, marginal glucose tolerance is also a risk factor for aortic disorders, so the need to correct postprandial hyperglycemia is also noted ( For example, refer to the following document 3). At present, various agents have been developed as therapeutic drugs for diabetes in the context of the rapid increase in the number of diabetic patients in recent years, and the use of Biguanide, Sulfonylurea, Membrane Sensitivity Enhancement and a- 312XP / invention manual (supplement) /94-07/94 ] 06583 1351400

葡萄糖苷酶抑制劑等糖尿病治療藥。但雙胍藥有乳酸酸中毒、磺醯尿素藥有低血糖、胰島素敏感性增強藥有浮腫等副作用，且亦有促進肥胖化之虞。又，為改善飯後高血糖係使用延遲小腸糖質消化、吸收之 α -葡萄糖苷酶抑制藥，而其中之一的阿卡玻糖（Acarbose)因適用於葡萄糖耐性異常者，而報告有其具有預防或延遲糖尿病發病之效果 (例如，參照下述文獻4)。但因 α -葡萄糖苷酶抑制藥不作用於攝取單糖葡萄糖所引起之血糖上升（例如，參照下述文獻5 )，故伴隨著最近飲食中糖質構成之改變，期望更廣泛之糖質吸收抑制作用。另外，最近推動新型糖尿病治療藥之研發，係藉由在腎臟阻止再吸收過剩之葡萄糖，以促進尿糖排泄，使血糖值減低（例如，參照下述文獻 6 )。又，報告有於腎臟近曲小管（proximal uriniferous tubules)之 S1 領域存在有 S G L T 2 (鈉依賴性葡萄糖輸送載體2 )，該S G L T 2主要與被腎小球（g 1 〇 m e r u 1 u s )過濾之葡萄糖之再吸收有關（例如，參照下述文獻7)。是故，藉由抑制人體S G L T 2以抑制腎臟中過剩之糖的再吸收，則可由尿排泄過剩之糖而使血糖值正常化。而由於此種尿糖排泄促進藥使過剩之糖由尿排泄，減少體内糖之蓄積，因此亦可期待其防止或減輕肥胖症之效果及利尿效果。更進一步，認為其對起因於高血糖症而隨糖尿病或肥胖症之進展而發病之各種相關疾病亦為有用。再者，已知於負責糖質吸收之小腸中存在S G L T 1 (鈉依賴 ⑧ 312XP/發明說明書(補件)/94-07/94106583 1351400 性葡萄糖輸送載體1)。又，報告有在因SGLT1先天性異常而功能不全之患者中，其葡萄糖與乳糖之吸收將為不良（例如，參照下述文獻8〜1 0 )，而確認了 S G L T 1與葡萄糖及乳糖之吸收有關（例如，參照下述文獻1 1及1 2 )。除此之外，在0 L E T F鼠或以鏈脲黴素誘發糖尿病氛方面，確認到S G L T 1 之 m R N A及蛋白質增加、葡萄糖等之吸收亢進等情況（例如，參照下述文獻1 3及1 4)。又，於糖尿病患者，通常其糖質之消化、吸收亢進，例如於人體小腸中’確認到S G L T 1A therapeutic drug for diabetes such as a glucosidase inhibitor. However, the bismuth drugs have lactic acidosis, sulfonium and urea drugs have hypoglycemia, insulin sensitivity-enhancing drugs have edema and other side effects, and also promote the obesity. In addition, in order to improve post-prandial hyperglycemia, an α-glucosidase inhibitor that delays digestion and absorption of small intestinal glycogen is used, and one of them is reported to be suitable for glucose tolerance. It has an effect of preventing or delaying the onset of diabetes (for example, refer to the following Document 4). However, since the α-glucosidase inhibitor does not act on the rise of blood glucose caused by the intake of monosaccharide glucose (for example, refer to the following Document 5), it is expected that a wider variety of saccharide absorption is desired along with changes in the composition of the saccharide in the recent diet. Inhibition. In addition, recently, research and development of a new type of diabetes therapeutic drug has been carried out by preventing the reabsorption of excess glucose in the kidney to promote the excretion of urine sugar and to lower the blood sugar level (for example, refer to the following document 6). Furthermore, it was reported that there is SGLT 2 (sodium-dependent glucose delivery carrier 2) in the S1 domain of the proximal uriniferous tubules, which is mainly filtered by the glomerulus (g 1 〇meru 1 us ). Resorption of glucose is related (for example, refer to Document 7 below). Therefore, by inhibiting the human body S G L T 2 to suppress the reabsorption of excess sugar in the kidney, the blood sugar can be normalized by excreting excess sugar from the urine. Since the urinary sugar excretion promoting drug excretes excess sugar from the urine and reduces the accumulation of sugar in the body, it is expected to prevent or reduce the effect of obesity and diuretic effect. Further, it is considered to be useful for various related diseases which are caused by the progression of diabetes or obesity due to hyperglycemia. Furthermore, it is known that S G L T 1 is present in the small intestine responsible for saccharide absorption (sodium dependent 8 312 XP / invention specification (supplement) / 94-07/94106583 1351400 glucose delivery vehicle 1). In addition, it is reported that in patients with dysfunction due to congenital abnormality of SGLT1, the absorption of glucose and lactose will be poor (for example, refer to the following documents 8 to 10), and the absorption of SGLT 1 and glucose and lactose is confirmed. For example (for example, refer to the following documents 1 1 and 1 2). In addition, in the case of 0 LETF mice or streptozotocin-induced diabetes, it has been confirmed that RNA and protein of SGLT 1 are increased, and absorption of glucose or the like is increased (for example, refer to the following documents 1 3 and 14). ). In addition, in diabetic patients, usually the digestion and absorption of saccharides, such as in the small intestine of the human body, confirms S G L T 1

之m R N A及蛋白質之高度表現的情況（例如，參照下述文獻 1 5 )。因此，認為藉由如抑制人體S G L T 1則可抑制小腸中葡萄糖等糖質之吸收而抑制血糖值之上升，尤其根據上述之作用機制以延遲糖質之吸收而可矯正飯後高血糖。從而，為減輕或消除上述問題，期望早曰研發出具有抑制人體 SGLT活性抑制作用之新穎作用機制之糖尿病治療藥。本發明記載之縮合雜環衍生物為一完全新穎之化合物，而關於該衍生物作為具有S G L T 1抑制活性及/或S G L T 2 抑制活性、於小腸抑制葡萄糖及乳糖之吸收、或於腎臟抑制再吸收過剩之葡萄糖的藥劑為有用者則未有任何報告。文獻 1 : The Diabetes Control and Complications Trial Research Group, 「N. Engl.J.Med. j , 1993 年 9 月，第 329 卷，第 14 號，p.977-986; 文獻 2 : li K P r 〇 s p e c t i v e D i a b e t e s S t u d y G r 〇 u p，「Lancet」， 1998 年 9 月，第 352 卷，第 9]3]號， 312XP/發明說明書(補件)/94-07/941065S3 ⑧ 1351400 P.837- 853 ；文獻 3 • 富永真琴 > 厂内分泌. 糖尿病料 J ， 2 0 0 1 年 11 月 > 第 13 卷，第5號， Ρ .534 -54 2 ；文獻 4 Jean- -Lou i is Ch i a s son 及其他5名 Γ > Lane e t j . 2 0 0 2 年 6 月 ) 第 359 卷 > 第9 3 2 3號， P· 2 0 7 2 - 2 0 7 7 ; 文獻 5 • 小裕之及其他 3 名，厂曰本營養· 食糧學會 ί忽 j ,1 992 年 9 第45卷，第 1號， P. 27 1 文獻 £ » . L u c i an 0 Ros sett i 及其他 4 名 } Γ j. ,C1 in In， v e ； st.. j ，1 987 年 5 月 t 第 79 卷 9 Ρ· 15 1 0 - 1 5 1 5 文獻 7 t _ Y o sh i k at S U K a n a i 及其他 4 名 > 厂 J. Cl i η . I η ν e s ΐ ·」， 1994 年1 月，第 93 卷， P. 3 9 7 - 4 0 4；文獻 8 馬場忠雄及其他1 名，厂別冊曰本臨床領域The case where m R N A and protein are highly expressed (for example, refer to the following document 1 5). Therefore, it is considered that, by inhibiting the human body S G L T 1 , the absorption of glucose such as glucose in the small intestine can be suppressed, and the increase in blood sugar level can be suppressed. In particular, the postprandial hyperglycemia can be corrected by delaying the absorption of the saccharide according to the above-described mechanism of action. Therefore, in order to alleviate or eliminate the above problems, it is desired to develop a diabetes therapeutic drug having a novel action mechanism for inhibiting the inhibition of human SGLT activity. The condensed heterocyclic derivative of the present invention is a completely novel compound, and the derivative has SGLT 1 inhibitory activity and/or SGLT 2 inhibitory activity, inhibits absorption of glucose and lactose in the small intestine, or inhibits resorption in the kidney. None of the agents for excess glucose were useful. Document 1: The Diabetes Control and Complications Trial Research Group, "N. Engl. J. Med. j, September 1993, Vol. 329, No. 14, p. 977-986; Document 2: li KP r 〇spective D iabetes S tudy G r 〇up, "Lancet", September 1998, Vol. 352, No. 9] 3], 312XP / Invention Manual (supplement) /94-07/941065S3 8 1351400 P.837- 853 Document 3 • Fu Yong Zhen Qin > Plant Endocrine. Diabetic Material J, November 2001 > Volume 13, No. 5, Ρ .534 -54 2 ; Document 4 Jean- -Lou i is Ch ias son And 5 other Γ > Lane etj. June 2002) Volume 359 > 9 3 2 3, P· 2 0 7 2 - 2 0 7 7 ; Document 5 • Xiao Yuzhi and others 3 Name, Factory 营养本营养·食食学会 ί忽 j , 1 992 9 Volume 45, No. 1, P. 27 1 Literature £ » . L uci an 0 Ros sett i and 4 other} Γ j. ,C1 In In, ve ; st.. j , 1 May 987, Vol. 79 9 Ρ· 15 1 0 - 1 5 1 5 Literature 7 t _ Y o sh ik at SUK anai and 4 other factories J. Cl i η . I η ν es ΐ ·", January 1994, Vol. 93, P. 3 9 7 - 4 0 4; Document 8 Zhongxiong and 1 other, the company's booklet in this clinical field

別症候群系列」，1 9 9 8年，第1 9號，p . 5 5 2 - 5 5 4 ; 文獻 9:笠原道弘及其他 2名，「最新醫學」，1996 φ 年1月，第51卷，第1號，p.84-90; 文獻 10: 土屋友房及其他1名，「日本臨床」，1997 年 8 月，第 55 卷，第 8 號，ρ· 2131 - 2139 ; 文獻 11:金井好克，「腎與透析」，1998年12月，第 4 5卷，臨時增刊號，p · 2 3 2 - 2 3 7 ; . 文獻 12: E.Turk 及其他 4 名，「Nature」，1991 年 3 月，第 3 5 0 號，p . 3 5 4 - 3 5 6 ; 文獻 13:Y.Fujita及其他 5 名「Diabetologia」， 1998 年，第 41 卷，p. 1 4 5 9 - 1 4 6 6 ; 312Χρ/發明說明書(補件)/94-07/94】06583 1351400 文獻 14:J.Dyer 及其他 5 名，「Biochem. Soc. Trans.」， 1997 年，第 25 卷，p. 479S ; 文獻 15:J.Dyer 及其他 4 名，「Am.J.Physiol.」，2002 年 2 月，第 282 卷，第 2 號，P.G241-G248; 【發明内容】Other syndrome series", 1989, No. 19, p. 5 5 2 - 5 5 4 ; Document 9: Sugawara Dao and two others, "The Latest Medicine", 1996 φ, January, Vol. 51 , No. 1, p.84-90; Document 10: Tsuchiya and other ones, "Japanese Clinical", August 1997, Vol. 55, No. 8, ρ·2131 - 2139; Document 11: Jinjing Hao Ke, "Kidney and Dialysis", December 1998, Vol. 45, Temporary Supplement, p · 2 3 2 - 2 3 7 ; . Document 12: E. Turk and 4 others, "Nature", 1991 March, No. 3, 0, p. 3 5 4 - 3 5 6 ; Document 13: Y. Fujita and five other "Diabetologia", 1998, Vol. 41, p. 1 4 5 9 - 1 4 6 6 ; 312Χρ/inventive manual (supplement)/94-07/94]06583 1351400 Document 14: J.Dyer and 5 others, "Biochem. Soc. Trans.", 1997, Vol. 25, p. 479S Document 15: J. Dyer and 4 others, "Am. J. Physiol.", February 2002, Vol. 282, No. 2, P. G241-G248; [Summary of the Invention]

本發明者等為發現表現人體SGLT活性抑制作用之化合物而專心研究，結果得知以下述一般式（I )表示之某種縮合雜環衍生物，可如下述表現人體S G L T 1及/或S G L T 2抑制活性，為具有血糖值上升抑制作用或血糖減低作用之優良藥劑，遂完成本發明。本發明係提供表現人體 SGLT活性抑制作用之新穎化合物、含有該化合物之醫藥組成物及其醫藥用途。亦即，本發明係關於： [1 ]以下述一般式（I )表示之縮合雜環衍生物或其藥理學上所容許之鹽或其前驅藥：The present inventors have intensively studied to find a compound which exhibits an inhibitory effect on the activity of human SGLT, and as a result, it has been found that a certain condensed heterocyclic derivative represented by the following general formula (I) can express human body SGLT 1 and/or SGLT 2 as follows. The inhibitory activity is an excellent agent having an action of suppressing an increase in blood sugar level or a function of lowering blood sugar, and the present invention has been completed. The present invention provides a novel compound which exhibits an inhibitory effect on human SGLT activity, a pharmaceutical composition containing the same, and a medical use thereof. That is, the present invention relates to: [1] a condensed heterocyclic derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof or a precursor thereof:

[式中： R1〜R4各自獨立為氫原子、羥基、胺基 '鹵素原子、Ch 烷基、Ch烷氧基、氰基、羧基、C2-7烷氧羰基、胺曱醯基、單或二（Ci-6烷）胺基、齒化（Ci-Β烷）基、羥（C，-6烷）基、氰 (C丨-6烷）基、羧（C丨-6烷）基、C2-7烷氧羰（C丨-6烷）基、胺甲 312XP/發明說明書(補件)/94-07/94106583 9 ⑧ 1351400Wherein R1 to R4 are each independently a hydrogen atom, a hydroxyl group, an amine group 'halogen atom, a Ch alkyl group, a Ch alkoxy group, a cyano group, a carboxyl group, a C2-7 alkoxycarbonyl group, an amine group, a single or two (Ci-6 alkane) amine group, dentate (Ci-decane) group, hydroxy (C, -6 alkyl) group, cyan (C丨-6 alkyl) group, carboxy (C丨-6 alkyl) group, C2 -7 alkoxycarbonyl (C丨-6 alkyl) group, amine A 312XP / invention specification (supplement) /94-07/94106583 9 8 1351400

醯（C丨-6烷）基 '胺（C丨-6烷）基、單或二（C丨-6烷）胺（Ci-6烷）基、鹵化（C丨-6烷氧）基、羥（Cl - 6烷氧）基 '羧（C丨-6烷氧）基、 C2-7烷氧羰（C，-6烷氧）基、胺甲醯（Ci-6烷氧）基、胺（Ci-6烷氡）基、單或二（Ci-6烷）胺（0-6烷氧）基、C3-7環烷基、C3-7 環烷氧基、C 3 - 7環烷（C，- 6烷）基或C 3 - 7環烷（C，- 6烷氧）基； R5及R6各自獨立為氫原子、羥基、鹵素原子、Ci-6烷基、 C2-6稀基、Ci-6块基、Cl-6烧氧基、C?-6稀氧基、〇1-6烧硫基、 C2-6烤硫基、鹵化（Cl-6烧）基、鹵化（Cl-6烧氧）基、鹵化（Cl-6 烷硫）基、羥（C丨-6烷）基、羥（C 2 - 6烯）基、羥（C丨-6烷氧）基、羥（0-6烷硫）基、羧基、羧（CU烷）基、羧（C2-6烯）基、羧 (C丨-6烷氧）基、羧（C丨-6烷硫）基、C2-7烷氧羰基、C2-7烷氧羰（CM烷）基' C2-7烷氧羰（C2-6烯）基、C2-7烷氧羰（0-6烷氧）基、C2-7烷氧羰（C丨-6烷硫）基、Cl-6烷亞磺醯基、C丨-6烷磺醯基、- U- V- W- N(R7)-Z、或可具有1〜3個選擇自下述取代基群α之任意基作為環取代基之下述取代基（i ) 〜（X X v i i i )： (i)C6-i。芳基、（ii)C6-i。芳基-Ο -、（iii)C6-i〇芳基-S -、 (iv)Ce-i。芳（Cl-6 烧）基、（V)C6-I。芳（Cl-6 烧氧）基、（vi)C6-i〇芳（Cm烷硫）基、（vii)雜芳基、（viii)雜芳基-0 - 、（ix) 雜芳基-S- 、（X)雜芳（C丨-6烷）基、（xi)雜芳（C丨-6烷氧）基、（X i i )雜芳（C 1 - 6 烷硫）基、（X i i i ) C 3 - 7 環烷基、（X i v ) C 3 - 7 環坑基 _ 0- 、（XV)C3-7 環烧基-S- ' (XVi)C3-7 環炫^(Cl-6 烷）基、（xvii)C3-7 環烷（Ch 烷氧）基、（xviii)C3-7 環烷（Ci-6 烧硫）基、（xix)雜環坑基、（XX)雜環统基-0- 、（xxi)雜 312XP/發明說明書(補件)/94-07/94106583 ⑧ 1351400 環烷基-S - 、（ x x i i )雜環烷（C，- 6烷）基、（x x i i i )雜環烷 (Ci-8炫•氧）基、（xxiv)雜環烧（Ci-6坑硫）基、（xxv)芳香族環狀胺基、（xxvi)芳香族環狀胺（Ci-6烷）基、（xxvii)芳香族環狀胺（C , - 6烷氧）基或（X X v i i i )芳香族環狀胺（C，- 6烷硫）基；Anthracene (C丨-6 alkyl)-amine (C丨-6 alkane) group, mono or di(C丨-6 alkane)amine (Ci-6 alkane) group, halogenated (C丨-6 alkoxy) group, Hydroxy (Cl-6 alkoxy)-carboxy (C丨-6 alkoxy), C2-7 alkoxycarbonyl (C, -6 alkoxy), amine formazan (Ci-6 alkoxy), amine (Ci-6 alkane), mono or di(Ci-6 alkyl)amine (0-6 alkoxy), C3-7 cycloalkyl, C3-7 cycloalkoxy, C 3 -7 naphthenic ( a C,-6 alkyl) group or a C 3 -7 cycloalkane (C,-6 alkoxy) group; each of R 5 and R 6 is independently a hydrogen atom, a hydroxyl group, a halogen atom, a Ci-6 alkyl group, a C 2-6 rare group, Ci-6 block group, Cl-6 alkoxy group, C?-6 diloxy group, 〇1-6 thio group, C2-6 baked thio group, halogenated (Cl-6) group, halogenated (Cl-6 Oxygen-based), halogenated (Cl-6 alkylthio) group, hydroxy (C丨-6 alkyl) group, hydroxy (C 2 - 6 ene) group, hydroxy (C丨-6 alkoxy) group, hydroxy (0- 6 alkylthio), carboxyl, carboxy (CU), carboxy (C2-6 a), carboxy (C丨-6 alkoxy), carboxy (C丨-6 alkylthio), C2-7 Oxycarbonyl, C2-7 alkoxycarbonyl (CM)-based 'C2-7 alkoxycarbonyl (C2-6 alkenyl), C2-7 alkoxycarbonyl (0-6 alkoxy), C2-7 Alkoxycarbonyl (C丨-6 alkylthio) group, Cl-6 alkylsulfinyl group, C丨-6 alkanesulfonyl group, -U-V-W-N(R7)-Z, or may have 1~ Three substituents (i) to (XX viii) selected from the arbitrary substituents of the following substituent group α as a ring substituent: (i) C6-i. Aryl, (ii) C6-i. Aryl-Ο-, (iii) C6-i〇 aryl-S-, (iv) Ce-i. Aromatic (Cl-6) base, (V) C6-I. Aromatic (Cl-6 alkoxy) group, (vi) C6-i aryl (Cm alkylthio) group, (vii) heteroaryl, (viii) heteroaryl-0 - , (ix) heteroaryl-S - (X) heteroaryl (C丨-6 alkane) group, (xi) heteroaryl (C丨-6 alkoxy) group, (X ii ) heteroaryl (C 1 - 6 alkylthio) group, (X iii C 3 - 7 cycloalkyl, (X iv ) C 3 - 7 ring pit _ 0- , (XV) C3-7 cycloalkyl-S- ' (XVi) C3-7 ring ^ ^ (Cl-6 Alkyl group, (xvii) C3-7 cycloalkane (Ch alkoxy) group, (xviii) C3-7 cycloalkane (Ci-6 sulfur-burning) group, (xix) heterocyclic pit group, (XX) heterocyclic ring system Base-0-, (xxi) 312XP/invention specification (supplement)/94-07/94106583 8 1351400 cycloalkyl-S-, (xxii) heterocycloalkane (C,-6 alkyl) group, (xxiii) Heterocycloalkane (Ci-8 Hyun), (xxiv) heterocyclic (Ci-6 pit sulfur), (xxv) aromatic cyclic amine, (xxvi) aromatic cyclic amine (Ci-6) Alkyl group, (xxvii) aromatic cyclic amine (C,-6 alkoxy) group or (XX viii) aromatic cyclic amine (C,-6 alkylthio) group;

U為、- S-、或單鍵（但U為-〇-或- S_時，V 及W不同時為單鍵）； V為可具有羥基之Ci-6伸烷基、C2-6伸烯基或單鍵；U is, -S-, or a single bond (but when U is -〇- or -S_, V and W are not single bonds at the same time); V is a Ci-6 alkyl group which may have a hydroxyl group, C2-6 extension Alkenyl or single bond;

W 為- CO- 、- S〇2 - 、- C(=NH) -或單鍵； Z為氫原子、C2-7烷氧羰基、C6->。芳（C2-7烷氧羰）基、曱醯基、-R、- COR8、- S〇2R8、- C0N(Rc)Rd、- CSN(Rc)RD、- S(hNHRA 或-C( = NR^W)!^ ; R7、RA、V及R°各自獨立為氫原子、可具有1〜5個選擇自下述取代基群点之任意基之Ci-6烷基或可具有1〜3 個選擇自下述取代基群 α 之任意基之下述取代基（xxix) 〜（X X X i i ): (xxix)Ce-i。芳基、（XXX)雜芳基、（xxxi)C3-7 環炫< 基或 (X X X i i )雜環炫^基；或，Z與R7鍵結並與鄰接之氮原子共同形成可具有1〜3 個選擇自下述取代基群α之任意基之脂環式胺基，或 Re與RD鍵結並與鄰接之氮原子共同形成可具有1〜3個選擇自下述取代基群α 之任意基之脂環式胺基； RB為C2-7烷氧羰基、Crc烷磺醯胺基、。芳磺醯胺基、可具有1〜5個選擇自下述取代基群/3 之任意基之烷 312XP/發明說明書(補件)/94-07/94106583 11 ⑧ 1351400 基或可具有1〜3個選擇自下述取代基群 α 之任意基之下述取代基（xxxiii)〜（xxxvi): (xxxiii)Ce-i。芳基 ' (xxxiv)雜芳基、（xxxv)C3-7 環燒基或 (xxxvi)雜環烷基；W is -CO-, -S〇2 -, -C(=NH)- or a single bond; Z is a hydrogen atom, a C2-7 alkoxycarbonyl group, C6->. Aromatic (C2-7 alkoxycarbonyl), fluorenyl, -R, -COR8, -S〇2R8, -C0N(Rc)Rd, -CSN(Rc)RD, -S(hNHRA or -C( = NR ^W)!^; R7, RA, V and R° are each independently a hydrogen atom, and may have 1 to 5 Ci-6 alkyl groups selected from any of the following substituent group points or may have 1 to 3 The following substituents (xxix) to (XXX ii ) are selected from any of the following substituent groups α: (xxix) Ce-i. aryl, (XXX) heteroaryl, (xxxi) C3-7 ring < or (XXX ii )heterocyclic group; or, Z and R7 are bonded to each other and form an alicyclic ring which may have 1 to 3 groups selected from the following substituent group α; The amine group, or Re, is bonded to RD and together with the adjacent nitrogen atom to form an alicyclic amine group which may have 1 to 3 groups selected from the following substituent group α; RB is a C2-7 alkoxycarbonyl group, Crc alkanesulfonylamino, arylsulfonylamino group, alkane 312XP which may have 1 to 5 groups selected from the following substituent group /3 / invention specification (supplement) /94-07/94106583 11 8 1351400 base or may have 1 to 3 substituents selected from any of the following substituent groups α . Xxxiii) ~ (xxxvi): (xxxiii) Ce-i aryl group '(xxxiv) heteroaryl, (xxxv) C3-7 cycloalkyl group or burning (XXXVI) heterocycloalkyl;

RE、RF及RG各自獨立為氫原子、氱基、胺曱醞基、Cz-7 6¾基、C 2 - 7炫氣幾基、C 6 - I。芳（C 2 - 7烧氧幾）基、硝基、C I - 6 炫黃酿基、胺磺醯基' 曱脒基（carbamimidoyl)或可具有1 〜5個選擇自下述取代基群/5之任意基之Ci-6烷基；或 RE與V鍵結形成伸乙基，或 RF與 Re鍵結並與鄰接之氮原子共同形成可具有選擇自下述取代基群α 之任意基之脂環式胺基； Q為- Cl-6伸统基-、伸烤基-、_Cz-6伸快基-、_Cl-6 伸炫基-〇-、-Cl-6 伸烧基-S-、_0-Cl-6 伸烧基-、_S_Cl-6 伸坑基-、-Cl-6伸烧基-〇 - Cl-6伸坑基__ Cl-6伸坑基-S - Cl-6 伸烷基-、-C0N(R8) -、- N(R8)C0 -、- Ci-6 伸烷基-C0N(R8) -或- C0N(R8) - Ci-6 伸炫基-; R8為氫原子或Ci-6烷基；環A為Cm。芳基或雜芳基；RE, RF and RG are each independently a hydrogen atom, a fluorenyl group, an amine fluorenyl group, a Cz-7 63⁄4 group, a C 2 - 7 singular group, and a C 6 - I group. Aromatic (C 2 -7 alkoxy) group, nitro, CI-6 flavonoid, carbamimidoyl or may have from 1 to 5 selected from the following groups of substituents/5 Any group of Ci-6 alkyl; or RE and V bonded to form an extended ethyl group, or RF and Re bonded together with an adjacent nitrogen atom to form a lipid which may have any group selected from the following substituent group α Cyclic amine group; Q is - Cl-6 stretching group -, stretching base -, _Cz-6 stretching fast group -, _Cl-6 stretching unit - 〇-, -Cl-6 stretching group - S-, _0-Cl-6 Stretching base-, _S_Cl-6 Stretching base-, -Cl-6 stretching base-〇-Cl-6 extension pit base__ Cl-6 extension pit base-S-Cl-6 alkylene Base-, -C0N(R8)-, -N(R8)C0-,-Ci-6alkyl-C0N(R8)- or -C0N(R8)-Ci-6exetyl-; R8 is a hydrogen atom Or Ci-6 alkyl; Ring A is Cm. Aryl or heteroaryl;

.為..for.

312XP/發明說明書(補件)/S>4-07/94 ] 065S3 ⑧ 1351400 RS為氫原子、Ci-6烷基、羥（1-6烷）基、C3-7環烷基或C3-7 環烷（C i - 6烷）基； G為以式312XP/Invention Manual (Supplement)/S>4-07/94] 065S3 8 1351400 RS is a hydrogen atom, a Ci-6 alkyl group, a hydroxy (1-6 alkyl) group, a C3-7 cycloalkyl group or a C3-7 Cycloalkane (C i - 6 alkane) group; G is a formula

或or

(G-2) 表示之基； E1為氫原子、氟原子或羥基； E2為氫原子' 氟原子、甲基或羥甲基； [取代基群α ](G-2) represents a group; E1 is a hydrogen atom, a fluorine atom or a hydroxyl group; E2 is a hydrogen atom 'a fluorine atom, a methyl group or a hydroxymethyl group; [substituent group α]

鹵素原子、羥基、胺基' C丨-6烷基、Ci-6烷氧基、ii化（C丨_6 烷）基、鹵化（（^-6烷氧）基、羥（Cm烷）基、C2-7烷氧羰（Ch 烷）基、羥（Cl-6烷氧）基、胺（CM烷）基、胺（Ci-6烷氧）基、單或二（Ci-6烷）胺基、單或二[羥（Ci-6烷）]胺基、Ci-S烷磺醯基、烷磺醯胺基、Ci-6烷磺醯胺（Ci-6烷）基、羧基、 C2-7烷氧羰基、胺磺醯（sulfamoyl)基及-C0N(RH) R1 [取代基群/5 ] 鹵素原子、經基、胺基、C丨-6炫< 氧基、C 1 - 6烧硫基、鹵化（C丨-6 烷氧）基、il化（C i - 6烷硫）基、羥（C ! - S烷氧）基、羥（C i - 6烷硫）基、胺（Ci-6烷氧）基、胺（Cm烷硫）基、單或二（Ci-6烷） 312XP/發明說明書(補件)/94-07/94106583 13 ⑧ 1351400 胺基、單或二[羥（Ci-6烷）]胺基、脲基、磺醯胺基、單或二（Cm烷）脲基、單或二[羥（Ch烷）]脲基、單或二（Ci-6 烷）磺醯胺基、單或二[羥（Ci-6烷）]磺醯胺基、C2-7醯基胺基、胺（Cz-7酿基胺）基、Cl-6坑項酿基、Cl-6坑續酿基胺基、胺曱醯（Ci-6烷磺醯基胺）基、羧基、C2-7烷氧羰基、-C0N(R") R1及可具有1〜3個選擇自下述取代基群α之任意基作為環取代基之下述取代基（xxxvii)〜（xxxxviii):Halogen atom, hydroxyl group, amine 'C丨-6 alkyl group, Ci-6 alkoxy group, ii (C丨_6 alkyl) group, halogenated ((1-6 alkoxy) group, hydroxy (Cm alkane) group , C2-7 alkoxycarbonyl (Ch alkyl) group, hydroxy (Cl-6 alkoxy) group, amine (CM alkyl) group, amine (Ci-6 alkoxy) group, mono or di(Ci-6 alkane) amine Base, mono or bis[hydroxy(Ci-6))amino, Ci-S alkanesulfonyl, alkanesulfonylamino, Ci-6 alkanesulfonamide (Ci-6 alkane), carboxyl, C2- 7 alkoxycarbonyl, sulfamoyl group and -C0N(RH) R1 [Substituent group/5] Halogen atom, trans group, amine group, C丨-6 Hyun < Oxyl, C 1 - 6 Sulfur-based, halogenated (C丨-6 alkoxy) group, ilylated (C i - 6 alkylthio) group, hydroxy (C s - S alkoxy) group, hydroxy (C i - 6 alkylthio) group, amine ( Ci-6 alkoxy), amine (Cm alkylthio), mono or di(Ci-6 alkane) 312XP / invention specification (supplement) /94-07/94106583 13 8 1351400 Amino, mono or di [hydroxy (Ci-6 alkane)]amino, ureido, sulfonylamino, mono or di(Cm alkane)urea, mono or bis[hydroxy(Ch)]ureido, mono or di(Ci-6 alkane) Sulfonamide, mono or bis[hydroxy(Ci-6 alkane)]sulfonamide Base, C2-7 mercaptoamine, amine (Cz-7-branthylamine) group, Cl-6 pit base, Cl-6 pit, amine group, amine oxime (Ci-6 alkanesulfonyl) An amine) group, a carboxyl group, a C2-7 alkoxycarbonyl group, -C0N(R") R1, and the following substituents (xxxvii) which may have 1 to 3 groups selected from the following substituent group α as a ring substituent; ~(xxxxviii):

(X X X v i i ) C 6 -1。芳基、（X X X v i i i ) C 6 -1 〇芳基-0-、 (XXXix)Ce-i。芳（Ci-6 烧氧）基、（XXXX)Ce-i。芳（Ci-6 院硫）基、（xxxxi)雜芳基、（xxxxii)雜芳基-0 - 、（xxxxiii)Ca-7 環院基、（xxxxiv)C3-7環烧基-0- 、（xxxxv)雜環烧基、 (xxxxvi)雜環烧基-0- 、（xxxxvii)脂環式胺基或 (X X X X v i i i )芳香族環狀胺基； R11與R1各自獨立為氫原子或可具有1〜3個選擇自下述取代基群 7 之任意基之烷基，或兩者鍵結並與鄰接之氮原子共同形成可具有1〜3個選擇自下述取代基群（5 之任意基之脂環式胺基； [取代基群T ] 鹵素原子、羥基、胺基、Cl-6烷氧基、鹵化（（^-6烷氧）基、羥（Ch烷氧）基、胺（Cm烷氧）基、單或二（Cm烷）胺基、單或二[羥（Cm烷）]胺基、脲基、磺醯胺基、單或二（Cn 烷）脲基、單或二[羥（Cm烷）]脲基、單或二（Ch烷）磺醯胺基、單或二[羥（C，- 6烷）]磺醯胺基、C2 -7醯基胺基 '胺（C 2 -7 醯基胺）基、C，- 6烷磺醯基、C ! - 6烷磺醯基胺基、胺曱醯（C，- 6 3】2XP/發明說明書(補件)/94-07/94】06583 14 ⑧ 1351400 烷磺醯基胺）基、羧基、C2-7烷氧羰基、胺磺醯基及-C0N(Rj) RK [取代基群5 ](X X X v i i ) C 6 -1. Aryl, (X X X v i i i ) C 6 -1 芳 aryl-0-, (XXXix) Ce-i. Aromatic (Ci-6 oxygenated) group, (XXXX) Ce-i. Fang (Ci-6 Institute sulfur), (xxxxi)heteroaryl, (xxxxii)heteroaryl-0 - , (xxxxiii)Ca-7 ring, (xxxxiv)C3-7cycloalkyl-0-, (xxxxv)heterocyclic alkyl, (xxxxvi)heterocyclic alkyl-0-, (xxxxvii) alicyclic amine group or (XXXX viii) aromatic cyclic amine group; R11 and R1 are each independently a hydrogen atom or may have 1 to 3 alkyl groups selected from any of the following substituent groups 7 or both bonded and formed together with adjacent nitrogen atoms may have 1 to 3 substituent groups selected from the following groups (5 Alicyclic amino group; [Substituent group T] Halogen atom, hydroxyl group, amine group, Cl-6 alkoxy group, halogenated ((1-6 alkoxy) group, hydroxy (Ch alkoxy) group, amine (Cm Alkoxy), mono or di(Cm alkane)amine, mono or bis[hydroxy(Cm) aminyl, ureido, sulfonylamino, mono or di(Cn alkane)urea, mono or di [ Hydroxy (Cm alkane)]ureido, mono or di(Ch alkane)sulfonylamino, mono or bis[hydroxy(C,-6 alkyl)]sulfonylamino, C2-7-decylamino'amine (C 2 -7 mercaptoamine), C,-6 alkanesulfonyl, C!-6 alkanesulfonylamino, amidoxime (C, - 6 3 2XP/Inventive Manual (Supplement)/94-07/94]06583 14 8 1351400 Alkylsulfonylamine), Carboxyl, C2-7 Alkoxycarbonyl, Aminesulfonyl and -C0N(Rj) RK [Substituents Group 5]

鹵素原子 '經基、胺基、Cl-6烧基、Ci- 6院氧基、鹵化（Ci- e 院）基、鹵化（Cl-6炫氧）基、經（Cl-6烧）基' C2-7烧氧幾（Cl-6 烷）基、羥（C,-6烷氧）基、胺（Ci-6烷）基、胺（L-6烷氧）基、單或二（Ci-6烷）胺基、單或二[羥（Ci-6烷）]胺基、0-6烷磺醯基、Ci-6烷磺醯基胺基、Ci-6烷磺醯基胺（Ci-6烷）基、羧基、C2-7烷氧羰基、胺磺醯基及-CON(V) RK …與 RK各自獨立為氫原子或可具有 1〜3個選擇自羥基、胺基、單或二（Ci-6烷）胺基、C2-7烷氧羰基及胺曱醯基之任意基之Cl-6烧基’或兩者鍵結並與鄰接之氮原子共同形成可具有1〜3個選擇自羥基 '胺基、單或二（1-6烷）胺基、0-6烷基、羥（Cl-6 烷）基、C2-7烷氧羰基、C2-7烷氧羰（(L-6烷）基及胺甲醯基之任意基之脂環式胺基。 [2 ]如前述[1 ]所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，其中，Q 為亞曱基、伸乙基、_ 0CH2_ 、_ C Η 2 0 - 、- S C Η 2 ~ 、- C Η 2 S -。 [3 ]如前述[2 ]所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，其中，Q為伸乙基。 [4 ]如前述[2 ]所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，其中，Q為亞甲基。 [5 ]如前述[1 ]〜[4 ]中任一項所記載之縮合雜環衍生物或 312ΧΡ/發明說明書(補件)/94-07/94106583 15 ⑧ 1351400 .其藥理學上容許之鹽或其前驅藥，其中，環Halogen atom 'trans group, amine group, Cl-6 alkyl group, Ci-6 gas, halogenated (Ci-e) base, halogenated (Cl-6 oxy) group, (Cl-6) base C2-7 aerobic (Cl-6 alkane) group, hydroxy (C, -6 alkoxy) group, amine (Ci-6 alkoxy) group, amine (L-6 alkoxy) group, mono or di (Ci- 6 alkyl)amino, mono or bis[hydroxy(Ci-6 alkane)]amino, 0-6 alkanesulfonyl, Ci-6 alkanesulfonylamino, Ci-6 alkanesulfonylamine (Ci- 6 alkyl), carboxy, C 2-7 alkoxycarbonyl, aminsulfonyl and -CON(V) RK ... and RK are each independently a hydrogen atom or may have 1 to 3 selected from a hydroxyl group, an amine group, a single or a second The (Ci-6 alkane)amino group, the C2-7 alkoxycarbonyl group and the C1-6 alkyl group of any group of the amine fluorenyl group or both bonded and formed together with the adjacent nitrogen atom may have 1 to 3 options. From hydroxy 'amine, mono or di(1-6 alkyl)amino, 0-6 alkyl, hydroxy (Cl-6 alkyl), C2-7 alkoxycarbonyl, C2-7 alkoxycarbonyl ((L- The condensed amino group of any one of the above-mentioned [1], or a pharmacologically acceptable salt thereof, or a precursor thereof, wherein Q is Aachen Ethyl, _ 0CH2_ , _ C Η 2 0 - , - SC Η 2 ~ , - C Η 2 S - [3] The condensed heterocyclic derivative described in the above [2] or its pharmacologically acceptable The condensed heterocyclic derivative or the pharmacologically acceptable salt thereof or the precursor thereof as described in the above [2], wherein Q is a methylene group, or a prodrug thereof [5] The condensed heterocyclic derivative according to any one of the above [1] to [4] or the 312 ΧΡ / invention specification (supplement) / 94-07/94106583 15 8 1351400. Pharmacologically acceptable Salt or its precursor, wherein the ring

為for

[6 ]如前述[1 ]〜[4 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，其中，環[6] The condensed heterocyclic derivative described in any one of the above [1] to [4], or a pharmacologically acceptable salt thereof or a precursor thereof, wherein the ring

為 X) [7 ]如前述[1 ]所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，其中，R5及R6各自獨立為氫原子、羥基、The condensed heterocyclic derivative or a pharmacologically acceptable salt thereof, or a prodrug thereof, according to the above [1], wherein each of R5 and R6 is independently a hydrogen atom or a hydroxyl group.

鹵素原子、C丨-6烧基、C2-6稀基、C2-6炔基、Cl-6炫·氧基、匚2-6稀氧基、0；1-6炫>硫基、〇2-6稀硫基、鹵化（〇丨-6烧）基、鹵化（Cl-6烧氧）基、鹵化（Cl-6烧硫）基、經（Cl-6炫）基、經 (C2-6烯）基、羥（Ci-6烷氧）基或羥（Ci-6烷硫）基。 [8 ]如前述[1 ]、[ 5 ]、[ 6 ]或[7 ]所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，其中，環A為苯環或《比咬環。 [9 ]如前述[1 ]〜[8 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥，其中，G為以式 16⑧ 312XP/發明說明書(補件)/94-07/94】06583 1351400Halogen atom, C丨-6 alkyl group, C2-6 weak group, C2-6 alkynyl group, Cl-6 dahdyloxy group, 匚2-6 diloxy group, 0; 1-6 dazzle > sulfur group, hydrazine 2-6 dilute sulfur, halogenated (〇丨-6) base, halogenated (Cl-6), halogenated (Cl-6 sulfur) base, (Cl-6) base, by (C2- 6 a)), hydroxy (Ci-6 alkoxy) or hydroxy (Ci-6 alkylthio) group. [8] The condensed heterocyclic derivative described in the above [1], [5], [6] or [7], or a pharmacologically acceptable salt thereof, or a precursor thereof, wherein the ring A is a benzene ring or Than the bite ring. [9] The condensed heterocyclic derivative or a pharmacologically acceptable salt thereof or a precursor thereof according to any one of the above [1] to [8], wherein G is a formula 168 312XP/invention specification (complement) Piece) /94-07/94]06583 1351400

HOHO

OH 表示之基。 [1 0 ] —種含有上述[1 ]〜[9 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥作為有效成分之醫藥组成物。The base of OH. [1 0 ] A pharmaceutical composition containing the condensed heterocyclic derivative according to any one of the above [1] to [9] or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient.

[1 1 ]—種含有上述[1 ]〜[9 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥作為有效成分之人體SGLT活性抑制劑。 [1 2 ]如前述[1 1 ]所記載之人體 S G L T活性抑制劑，其中， SGLT 為 SGLT1 及 / 或 SGLT2。 [1 3 ]如前述[1 1 ]所記載之人體S G L T活性抑制劑，其為飯後高血糖抑制劑。 [1 4 ]如前述[1 1 ]所記載之人體S G L T活性抑制劑，其為由高血糖症所引起疾病之預防或治療劑。 [1 5 ]如前述[1 4 ]所記載之人體S G L T活性抑制劑，其中，由高血糖症所引起之疾病為選擇自糖尿病、葡萄糖耐性異常、糖尿病性併發症、肥胖症、高胰島素血症、高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常、動脈粥樣硬化症、高血壓、鬱血性心竭、浮腫 '高尿酸血症及痛風等所構成群組中之疾病。 [1 6 ]如前述[1 1 ]所記載之人體S G L T活性抑制劑，其為阻止葡萄糖财性異常者轉移為糖展病之轉移阻止劑。 [1 7 ]如前述[1 0 ]所記載之醫藥組成物，其中，劑型為緩釋 312XP/發明說明書(補件)/9‘〇7/94106583 17 ⑧ 1351400 性製劑。 [1 8 ]如前述[1 1 ]所記載之人體S G L T活性抑制劑，其中，劑型為緩釋性製劑。 [1 9 ] 一種飯後高血糖之抑制方法，係包含以有效量投予前述[1 ]〜[9 ]任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥。[1 1 ] A human SGLT activity inhibitor comprising the condensed heterocyclic derivative according to any one of the above [1] to [9] or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient. [1] The human S G L T activity inhibitor according to the above [1 1], wherein the SGLT is SGLT1 and/or SGLT2. [1 3] The human S G L T activity inhibitor according to the above [1 1], which is a postprandial hyperglycemia inhibitor. [1] The human S G L T activity inhibitor according to the above [1 1 ], which is a prophylactic or therapeutic agent for a disease caused by hyperglycemia. [1] The human SGLT activity inhibitor according to the above [1 4], wherein the disease caused by hyperglycemia is selected from diabetes, glucose tolerance abnormality, diabetic complication, obesity, hyperinsulinemia. , hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis, hypertension, septic heart disease, edema, hyperuricemia, gout, etc. The disease. [1] The human S G L T activity inhibitor according to the above [1 1], which is a metastasis preventing agent which prevents metastasis of a glucose-conserving abnormality and which is transferred to a glucosaccharide disease. [1] The pharmaceutical composition according to the above [10], wherein the dosage form is sustained release 312XP/invention specification (supplement)/9'〇7/94106583 17 8 1351400. [1] The human S G L T activity inhibitor according to the above [1 1], wherein the dosage form is a sustained release preparation. [1 9 ] A method for inhibiting hyperglycemia after a meal, which comprises administering the condensed heterocyclic derivative described in any one of the above [1] to [9] or a pharmacologically acceptable salt thereof or a precursor thereof medicine.

[2 0 ] —種高血糖症所引起疾病之預防或治療方法，係包含以有效量投予前述[1 ]〜[9 ]任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥。 [2 1 ]如上述[2 0 ]所記載之預防或治療方法，其中，高血糖症所引起之疾病為選擇自糖尿病、葡萄糖耐性異常 '糖尿病性併發症、肥胖症、高姨島素血症、高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常、動脈粥樣硬化症' 高血壓、營血性心竭、浮腫、高尿酸血症及痛風等所構成群組中之疾病。 [2 2 ] —種阻止葡萄糖耐性異常者轉移為糖尿病之轉移阻止方法，包含以有效量投予前述[1 ]〜[9 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥。 [2 3 ] —種用以製造飯後高血糖抑制用醫藥組成物之前述[1 ] 〜[9 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥之用途。 [2 4 ] —種用以製造高血糖症所引起疾病之預防或治療用醫藥組成物之前述[1 ]〜[9 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥之用途。 3 ] 2XP/發明說明書(補件)/94-07/94 ] 06583 18 ⑧ 1351400 [25]如上述[24]項所記載之用途，其中，由高血糖症所引起之疾病為選擇自糖尿病、葡萄糖耐性異常 '糖尿病性併發症、肥胖症、高膝島素血症、高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常 '動脈粥樣硬化症、高血壓、繁血性心竭、浮腫 '高尿酸血症及痛風等所構成群組中之疾病。[2 0 ] A method for preventing or treating a disease caused by hyperglycemia, which comprises administering the fused heterocyclic derivative described in any one of the above [1] to [9] in an effective amount or pharmacologically acceptable thereof Salt or its precursor. [2] The method for prevention or treatment according to the above [2], wherein the disease caused by hyperglycemia is selected from diabetes, abnormal glucose tolerance, diabetic complications, obesity, and sputum , hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis 'hypertension, blood stasis, edema, hyperuricemia and gout The disease. [2 2 ] A method for preventing metastasis in which a person with impaired glucose tolerance is transferred to diabetes, comprising administering the condensed heterocyclic derivative described in any one of the above [1] to [9] or pharmacologically thereof in an effective amount. Permissible salt or its precursor. [2] A condensed heterocyclic derivative or a pharmacologically acceptable salt thereof, or a precursor thereof, of the pharmaceutically acceptable salt described in any one of the above [1] to [9], which is used in the manufacture of a pharmaceutical composition for suppressing hyperglycemia after a meal. The use of medicine. [2] A condensed heterocyclic derivative according to any one of the above [1] to [9], which is a pharmaceutical composition for the prophylaxis or treatment of a disease caused by hyperglycemia, or a pharmacologically acceptable thereof The use of the salt or its precursor. 3] 2XP/Inventive Manual (Supplement)/94-07/94] 06583 18 8 1351400 [25] The use according to the above [24], wherein the disease caused by hyperglycemia is selected from diabetes, Abnormal glucose tolerance 'diabetic complications, obesity, hyperkalemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism' atherosclerosis, hypertension, complication A disease in a group consisting of bloody exhaustion, edema, hyperuricemia, and gout.

[2 6 ] —種用以製造阻止葡萄糖耐性異常者轉移為糖尿病之轉移阻止用醫藥組成物之前述[1 ]〜[9 ]中任一項所記載之縮合雜環衍生物或其藥理學上容許之鹽或其前驅藥之用途。 [2 7 ]如上述[1 0 ]所記載之醫藥組成物，係組合選擇自由胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 B抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇（D-chiroinositol)'肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1、升糖素樣胜肽-1類似物、升糖素樣胜肽-1促效劑、香樹素（a m y 1 i η )'香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、後期糖化最终產物 (advanced glycation endproducts )生成抑制劑 '蛋白質激酶C抑制劑、τ -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑、轉錄因子NF - λ; B抑制劑、脂質過氧化酶抑制劑、 312XP/發明說明書(補件)/94-07/94106583 19 ⑧ 1351400[2 6 ] A condensed heterocyclic derivative according to any one of the above [1] to [9], or a pharmacologically active composition thereof, for use in the manufacture of a pharmaceutical composition for preventing metastasis of a glucose-tolerant person The use of the salt or its precursor. [2 7] The pharmaceutical composition according to the above [10], which is a combination of a free insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretion promoter, an SGLT2 activity inhibitor, an insulin or an insulin analog , Glucagon Receptor Antagonist, Insulin Receptor Kinase Stimulant, Tripeptidase II Inhibitor, Dipeptidase IV Inhibitor, Protein Tyrosine Phosphatase 1 B Inhibitor, Hepatic Glycophosphorylase Inhibitor, Glucose -6-phosphatase inhibitor, fructose diphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic glucose stimulating inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, Glycoglycan-like peptide-1, glycoside-like peptide-1 analog, glycoside-like peptide-1 agonist, fragrant tree (amy 1 i η )' fragrant tree analog, fragrant tree An agonist, aldose reductase inhibitor, advanced glycation endproducts production inhibitor 'protein kinase C inhibitor, tau-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF - λ; B inhibitor, lipid peroxidase inhibition Agents, 312XP / Manual (complement member) invention / 94-07 / 94106583 19 ⑧ 1351400

N - 乙 SS 化 -α - 連結酸性二肽分解酶 (N-acetylated-ύ： - linked-acid dipeptidase)抑制劑、肤島素樣生長因子-I、血小板來源生長因子、血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉驗衍生物 '尿核苷、5 -羥基-1-甲基乙内醯脲、EGB - 761、必莫克默（bimoclomol)、舒得塞（sulodexide)、 Y- 128、止瀉劑、瀉劑、羥甲基戊二醯輔酶A還原酶抑制劑、纖維酸衍生物、石3 -腎上腺素受體促效劑、醯基輔酶A :膽固醇醞基轉移酶抑制劑、丙丁酚（p r 〇 b u c ο 1 )、甲狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑 '肉鹼棕櫚醯基轉移酶抑制劑、鯊稀合成酶抑制劑、低比重脂蛋白受體增強劑、菸鹼酸衍生物、膽计酸吸附劑、鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移蛋白抑制劑 '食慾抑制劑、血管升壓素轉移酶抑制劑、中性肽鏈内切酶抑制劑、血管升壓素I I受體拮抗劑、内皮素轉移酶抑制劑、内皮素受體拮抗劑、利尿劑、鈣離子拮抗劑、血管擴張性降血壓劑、交感神經阻斷劑、中樞性降血壓劑、α 2 -腎上腺素受體促效劑、抗血小板劑、尿酸生成抑制劑、尿酸排泄促進劑及尿鹼性化劑所組成群組中之至少1種藥劑而成。 [2 8 ]如上述[1 1 ]所記載之人體S G L Τ活性抑制劑，係組合選擇自由胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、S G L Τ 2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽 312ΧΡ/發明說明書(補件)/94-07/94 ] 06583 20 ⑧ 1351400 酶1 I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 B 抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇、肝51合成酵素激酶-3抑制劑、升糖素樣胜肽-1、升糖素樣胜肽-1 類似物、升糖素樣胜肽-1 促效劑、香樹素、香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、後期糖化最終產物生成抑制劑、蛋白質激酶C抑制劑、7 -胺基丁酸受體拮抗劑、鈉離子通道N-acetylated-α-linked N-acetylated-ύ:-linked-acid dipeptidase inhibitor, skin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog , epithelial growth factor, nerve growth factor, meat test derivative 'urine nucleoside, 5-hydroxy-1-methyl carbendazim, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheal agent, laxative, hydroxymethyl glutaraldehyde coenzyme A reductase inhibitor, fibric acid derivative, stone 3 - adrenergic receptor agonist, 醯Kyethase A: cholesterol thiol transferase Inhibitor, probucol (pr 〇buc ο 1 ), thyroid receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor 'carnitine Palmitoyltransferase inhibitor, shark dilase inhibitor, low specific gravity lipoprotein receptor enhancer, nicotinic acid derivative, biliary acid adsorbent, sodium conjugated bile acid transfer factor inhibitor, cholesterol ester transfer protein Inhibitor's appetite suppressant, Vasopressin transferase inhibitor, neutral endopeptidase inhibitor, vasopressin II receptor antagonist, endothelin transferase inhibitor, endothelin receptor antagonist, diuretic, calcium antagonist , vasodilator hypotensive agent, sympatholytic blocker, central hypotensive agent, α 2 -adrenergic receptor agonist, antiplatelet agent, uric acid production inhibitor, uric acid excretion promoter and urine alkaline agent At least one of the components in the group is formed. [2] The human SGL Τ activity inhibitor according to the above [1 1 ], which is a combination of a free insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretion promoter, an SGL Τ 2 activity inhibitor, Insulin or insulin analogues, glycoside receptor antagonists, insulin receptor kinase stimulants, tripeptide 312ΧΡ/invention specification (supplement)/94-07/94] 06583 20 8 1351400 enzyme 1 I inhibitor, dipeptide Enzyme IV inhibitor, protein tyrosine phosphatase 1 B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose diphosphatase inhibitor, pyruvate dehydrogenase inhibitor, glycogen Neonatal Inhibitor, D-Hand Inositol, Liver 51 Synthase Kinase-3 Inhibitor, Glycoglycan-like Peptide-1, Glycoglycan-like Peptide-1 Analog, Glycoglycan-like Peptide-1 Agent, fragrant tree, auxin analogue, auxin agonist, aldose reductase inhibitor, late glycation end product production inhibitor, protein kinase C inhibitor, 7-aminobutyric acid receptor antagonist Sodium ion channel

拮抗劑、轉錄因子NF - /c B抑制劑、脂質過氧化酶抑制劑、水-乙醯化-α -連結酸性二肽酶抑制劑、胰島素樣生長因子-I、血小板來源生長因子 '血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉驗衍生物、尿核苷、 5 -羥基-1 -曱基乙内醯脲、E G Β - 7 6 1、必莫克默、舒得塞、Υ - 1 2 8、止瀉劑、瀉劑、羥曱基戊二醯輔酶Α還原酶抑制劑、纖維酸衍生物、/3 3 -腎上腺素受體促效劑、乙醯基輔酶 A :膽固醇醯基轉移酶抑制劑、丙丁酚、甲狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、肉鹼棕橺醯基轉移酶抑制劑、：¾:烯合成酶抑制劑、低比重脂蛋白受體增強劑、菸鹼酸衍生物、膽汁酸吸附劑、鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移蛋白抑制劑、食慾抑制劑、血管升壓素轉換酶抑制劑 '中性肽鏈内切酶抑制劑 '血管升壓素I I受體拮抗劑、内皮素轉移酶抑制劑、内皮素受體拮抗劑、利尿劑、鈣離子拮抗劑、血管擴張性降血壓劑、 312XP/發明說明書(補件)/94-(W94106583 21 ⑧ 1351400 交感神經阻斷劑、中框性降血壓劑' α 2 -腎上腺素受體促效劑、抗血小板劑、尿酸生成抑制劑 '尿酸排泄促進劑及尿鹼性化劑所組成群組中之至少1種藥劑而成。Antagonists, transcription factor NF- /c B inhibitors, lipid peroxidase inhibitors, water-acetylated-α-linked acid dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor' platelet source Growth factor analogs, epithelial growth factor, nerve growth factor, meat test derivatives, uridine, 5-hydroxy-1-mercaptoinouramide, EG Β - 7 6 1 , 必莫克默,舒德塞, Υ - 1 2 8, antidiarrheal, laxative, hydroxypurine quinone quinone coenzyme quinone reductase inhibitor, fibric acid derivative, /3 3 -adrenergic receptor agonist, acetamyl acetylase A: Cholesterol thiol transferase inhibitor, probucol, thyroid receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palm Thiol transferase inhibitor, 3⁄4: ene synthase inhibitor, low specific gravity lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium conjugated bile acid transfer factor inhibitor, cholesterol ester transfer protein Inhibitor, appetite suppressant, vasopressin Invertase inhibitor 'neutral endopeptidase inhibitor' vasopressin II receptor antagonist, endothelin transferase inhibitor, endothelin receptor antagonist, diuretic, calcium antagonist, vasodilatability Antihypertensive agent, 312XP/invention specification (supplement)/94-(W94106583 21 8 1351400 sympathetic blocker, mesogenic hypotensive agent' α 2 -adrenergic receptor agonist, antiplatelet agent, uric acid production The inhibitor is composed of at least one of a group consisting of a uric acid excretion promoting agent and a urine alkalizing agent.

[2 9 ]如上述[1 9 ]所記載之飯後高血糖抑制方法，係包含組合選擇自由胰島素敏感性增強劑、糖吸收抑制劑、雙脈藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶 I Β抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇、肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1、升糖素樣胜肽-1類似物、升糖素樣胜肽-1 促效劑、香樹素、香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、後期糖化最終產物生成抑制劑、蛋白質激酶C抑制劑、τ -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑、轉錄因子NF - /c Β抑制劑、脂質過氧化酶抑制劑、水-乙醯化-α -連結酸性二肽酶抑制劑、胰島素樣生長因子-I、血小板來源生長因子、血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉驗衍生物、尿核苷、 5 -羥基-1 -甲基乙内醯脲、E G Β - 7 61、必莫克默、舒得塞、Υ - 1 2 8、止瀉劑、瀉劑、羥甲基戊二醯輔酶Α還原酶抑制劑、纖維酸衍生物、泠3 -腎上腺素受體促效劑、醯基輔酶 A :膽固醇醯基轉移酶抑制劑、丙丁酚、甲狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘 312XP/發明說明書(補件)/94-〇7/941〇6583 22 ⑧ 1351400 油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、肉鹼棕櫚醒基轉移酶抑制剞、鯊歸合成酶抑制劑、低比重脂蛋白受趙增強劑、菸鹼酸衍生物、膽汁酸吸附劑、鈉共軛膽汁酸轉[2 9] The postprandial hyperglycemia inhibiting method according to the above [1 9], which comprises a combination of a free insulin sensitivity enhancer, a sugar absorption inhibitor, a double pulse drug, an insulin secretion promoter, an SGLT2 activity inhibitor, Insulin or insulin analogues, glycosidic receptor antagonists, insulin receptor kinase stimulators, tripeptidase II inhibitors, dipeptidase IV inhibitors, protein tyrosine phosphatase I Β inhibitors, glycogen phosphorylation Enzyme inhibitors, glucose-6-phosphatase inhibitors, fructose diphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic glycosity inhibitors, D-hand inositol, glycogen synthase kinase-3 inhibitors, Glycoglycan-like peptide-1, glycoside-like peptide-1 analog, glycoside-like peptide-1 agonist, fragrant tree, fragrant tree analog, auxin agonist, aldehyde Glycoreductase inhibitors, late glycation end product production inhibitors, protein kinase C inhibitors, tau-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- /c Β inhibitors, lipid peroxidation Enzyme inhibitor, water-acetylated-α-linked acid II Enzyme inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epithelial proliferation factor, nerve growth factor, meat derivative, urinary nucleoside, 5-hydroxy-1-methylethyl Urea urea, EG Β - 7 61, must Mokmer, Shu Desai, Υ - 1 2 8, antidiarrheal agent, laxative, hydroxymethyl pentane quinone coenzyme Α reductase inhibitor, fibric acid derivative, 泠3 - adrenergic receptor agonist, 醯Kyethase A: cholesterol thiol transferase inhibitor, probucol, thyroid receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsome triglyceride 312XP / Description of the invention (supplement)/94-〇7/941〇6583 22 8 1351400 Oil-transfer protein inhibitor, lipoxygenase inhibitor, carnitine palme-base transferase inhibitor, scorpion synthase inhibitor, low specific gravity Lipoprotein is regulated by Zhao enhancer, nicotinic acid derivative, bile acid adsorbent, sodium conjugated bile acid

移因子抑制劑、膽固醇酯轉移蛋白抑制劑、食慾抑制劑、血管升壓素轉移酶抑制劑、中性肽鏈内切酶抑制劑、血管升壓素I I受體拮抗劑' 内皮素轉移酶抑制劑、内皮素受體拮抗劑、利尿劑、鈣離子拮抗劑、血管擴張性降血壓劑' 交感神經阻斷劑、中梅性降血壓劑、α 2 -腎上腺素受體促效劑、抗血小板劑、尿酸生成抑制劑、尿酸排泄促進劑及尿鹼性化劑所組成群組中之至少1種藥劑並進行投予。 [3 0 ]如上述[2 0 ]所記載之高血糖症所引起疾病之預防或治療方法，係包含組合選擇自由胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT 2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 Β抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝耱新生抑制劑、D -手肌醇、肝餹合成酵素激酶-3抑制劑、升糖素樣胜肽-1、升糖素樣胜肽-1類似物、升糖素樣胜肽-1促效劑、香樹素、香樹素類似物、香樹素促效劑、酸糖還原酶抑制劑、後期糖化最終產物生成抑制劑 '蛋白質激酶C抑制劑、Τ -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑、轉錄因子NF - /c Β抑制劑、脂質過氧化酶抑制劑、水-乙醯化-α -連結酸性二肽酶抑制 312ΧΡ/發明說明書(補件)/94-07/94丨06583 23 ⑧ 1351400 劑、姨島素樣生長因子_ i、血小板來源生長因子、血小扳來源生長因子類似物、上皮增殖因子、神經生長因子、肉鹼衍生物' 尿核苷' 5 -羥基-1 -甲基乙内醯脲、Transfer factor inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, vasopressin transferase inhibitor, neutral endopeptidase inhibitor, vasopressin II receptor antagonist' endothelin transferase inhibition Agent, endothelin receptor antagonist, diuretic, calcium antagonist, vasodilator hypotensive agent' sympathetic blocker, Chinese plum hypotensive agent, α 2 -adrenergic receptor agonist, antiplatelet At least one agent selected from the group consisting of a dose, a uric acid production inhibitor, a uric acid excretion promoter, and a urinary alkalizing agent is administered. [3 0] The method for preventing or treating a disease caused by hyperglycemia as described in the above [2 0], comprising a combination of a free insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretion promoter, and an SGLT 2 activity inhibitors, insulin or insulin analogues, glycosidic receptor antagonists, insulin receptor kinase stimulators, tripeptidase II inhibitors, dipeptidase IV inhibitors, protein tyrosine phosphatase 1 Β inhibitors , hepatic glucose phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose diphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic neonatal neonatal inhibitor, D-hand inositol, hepatic synthase kinase -3 inhibitor, glycoside-like peptide-1, glycoside-like peptide-1 analog, glycoside-like peptide-1 agonist, fragrant tree, fragrant tree analog, fragrant tree Agonists, acid sugar reductase inhibitors, late glycation end product production inhibitors 'protein kinase C inhibitors, Τ-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF - /c Β inhibition Agent, lipid peroxidase inhibitor, water-acetone -α-linked acid dipeptidase inhibition 312ΧΡ/invention specification (supplement)/94-07/94丨06583 23 8 1351400 agent, 姨岛素-like growth factor _ i, platelet-derived growth factor, blood platelet-derived growth factor Analogs, epithelial proliferation factor, nerve growth factor, carnitine derivative 'urine nucleoside' 5-hydroxy-1 -methylhydantoin,

EG B - 7 6 1、必莫克默 '舒得塞、Y - 1 2 8、止瀉劑、瀉劑、羥曱基戊二醯輔酶A還原酶抑制劑、纖維酸衍生物、/9 3 -賢上腺素受體促效劑、醯基輔酶 A :膽固醇醯基轉移酶抑制劑' 丙丁酚、甲狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、肉鹼棕櫊醯基轉移酶抑制劑、鯊烯合成酶抑制劑、低比重脂蛋白受體增強劑、菸鹼酸衍生物 '膽汁酸吸附劑、鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移蛋白抑制劑、食慾抑制劑、血管升壓素轉移酶抑制劑、中性肽鏈内切酶抑制劑、血管升壓素I I受體拮抗劑' 内皮素轉移酶抑制劑、内皮素受體拮抗劑、利尿劑、鈣離子拮抗劑、血管擴張性降血壓劑、交感神經阻斷劑、中框性降血壓劑、α 2 -腎上腺素受體促效劑、抗止小板劑、尿酸生成抑制劑、尿酸排泄促進劑及尿鹼性化劑所組成群組中之至少1種藥劑並進行投予。 [3 1 ]如上述[2 2 ]所記載之阻止葡萄糖耐性異常者轉移為糖尿病之轉移阻止方法，係包含組合選擇自由胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2 活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 B抑制劑、肝醣磷酸化酶抑制 ⑧ 312XP/發明說明書(補件)/94_07/94106583 1351400EG B - 7 6 1. Bummomer's Shudesai, Y-1 2 8, antidiarrheal, laxative, hydroxypurine quinone coenzyme A reductase inhibitor, fibric acid derivative, /9 3 - adrenergic receptor agonist, 醯Kymase A: cholesterol thiol transferase inhibitor' propofol, thyroid receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride Transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyl transferase inhibitor, squalene synthetase inhibitor, low specific gravity lipoprotein receptor enhancer, nicotinic acid derivative 'bile acid adsorbent, Sodium conjugated bile acid transfer factor inhibitor, cholesteryl ester transfer protein inhibitor, appetite suppressant, vasopressin transferase inhibitor, neutral endopeptidase inhibitor, vasopressin II receptor antagonist Endothelin-transferase inhibitors, endothelin receptor antagonists, diuretics, calcium ion antagonists, vasodilators, sympathomimetic blockers, mesogenic hypotensive agents, α 2 -adrenergic receptors Agent, anti-small platelet, uric acid production inhibitor, uric acid At least one of the group consisting of a venting accelerator and a urinary alkalizing agent is administered and administered. [3 1] The method for preventing metastasis of metastasis to diabetes caused by abnormal glucose tolerance as described in the above [2 2], comprising a combination of a free insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretion promoter, SGLT2 activity inhibitor, insulin or insulin analogue, glycosidic receptor antagonist, insulin receptor kinase stimulator, tripeptidase II inhibitor, dipeptidase IV inhibitor, protein tyrosine phosphatase 1 B inhibitor , hepatic glucose phosphorylase inhibition 8 312XP / invention manual (supplement) /94_07/94106583 1351400

劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙嗣酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇 '肝醣合成酵素激酶-3抑制劑 '升糖素樣胜肽-1、升糖素樣胜肽-1類似物、升糖素樣胜肽-1促效劑 '香樹素、香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、後期糖化最终產物生成抑制劑、蛋白質激酶C抑制劑、7 -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑、轉錄因子NF - /c B抑制劑、脂質過氧化酶抑制劑、介-乙醯化-α -連結酸性二肽分解酶抑制劑、胰島素樣生長因子-I、血小板來源生長因子、血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉給衍生物、尿核苦、5 -經基-I -曱基乙内醯脲、E G Β - 7 61、必莫克默、舒得塞' Υ - 1 2 8、止瀉劑、瀉劑、羥甲基戊二醯輔酶Α還原酶抑制劑 '纖維酸衍生物、 /3 .3 -腎上腺素受體促效劑、醯基輔酶A :膽固醇醯基轉移酶抑制劑、丙丁酚、曱狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑 '肉鹼棕櫊醯基轉移酶抑制劑、鯊烯合成酶’抑制劑、低比重脂蛋白受體增強劑、於驗酸衍生物、膽汁酸吸附劑、鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移蛋白抑制劑、食慾抑制劑、血管升壓素轉移酶抑制劑、中性肽鏈内切酶抑制劑、血管升壓素I I受體拮抗劑、内皮素轉移酶抑制劑、内皮素受體拮抗劑 '利尿劑、鈣離子拮抗劑、血管擴張性降血壓劑、交感神經阻斷劑、中樞性降血壓劑、α 2 -賢上腺素受體促效劑、抗血小板劑、尿酸生 3 ] 2ΧΡ/發明說明書(補件)/94-07/94106583 25 ⑧ 1351400 成抑制劑、尿酸排泄促進劑及尿鹼性化劏所組成群組中之至少1種藥劑並進行投予。Agent, glucose-6-phosphatase inhibitor, fructose diphosphatase inhibitor, propionate dehydrogenase inhibitor, hepatic glucose stimulating inhibitor, D-hand inositol 'hepatic glycogen synthase kinase-3 inhibitor' Glycogen-like peptide-1, glycoside-like peptide-1 analog, glycoside-like peptide-1 agonist 'fragrant tree, fragrant tree analog, auxin agonist, aldose Reductase inhibitor, late glycation end product production inhibitor, protein kinase C inhibitor, 7-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF- /c B inhibitor, lipid peroxidase Inhibitor, inter-acetylated-α-linked acidic dipeptide-degrading enzyme inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epithelial growth factor, nerve growth factor, meat derived Substance, urinary nucleus, 5-cyano-I-mercaptoinouramide, EG Β - 7 61, must Mokmer, Shu Desai ' Υ - 1 2 8 , antidiarrheal, laxative, hydroxymethyl Alkyl quinone coenzyme quinone reductase inhibitor 'fibric acid derivative, /3.3-adrenergic receptor agonist, 醯 Kiev A: cholesterol thiol transferase inhibitor, probucol, sputum receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor Carnitine palmitoyl transferase inhibitor, squalene synthetase inhibitor, low specific gravity lipoprotein receptor enhancer, acid test derivative, bile acid adsorbent, sodium conjugated bile acid transfer factor inhibitor, cholesterol Ester transfer protein inhibitors, appetite suppressants, vasopressin transferase inhibitors, neutral endopeptidase inhibitors, vasopressin II receptor antagonists, endothelin-transferase inhibitors, endothelin receptors Antagonist 'diuretic, calcium antagonist, vasodilator hypotensive agent, sympatholytic blocker, central hypotensive agent, α 2 - adrenergic receptor agonist, antiplatelet agent, uric acid 3 2ΧΡ/Invention Manual (Supplement)/94-07/94106583 25 8 1351400 At least one agent selected from the group consisting of an inhibitor, a uric acid excretion promoter, and a urinary alkaline bismuth is administered.

[3 2 ] —種用以製造飯後高血糖抑制用醫藥組成物之用途，係應用（A )上述[1 ]〜[9 ]項中任一項所記載之缩合雜環衍生物或其藥理學上所容許之鹽或其前驅藥，及（B)選擇自由胰島素敏感性增強劑、糖吸收抑制劑' 雙胍藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶 II 抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 B抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇、肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1、升糖素樣胜肽-1類似物、升糖素樣胜肽-1促效劑、香樹素、香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、後期糖化最終產物生成抑制劑、蛋白質激酶 C 抑制劑、7 -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑、轉錄因子NF - /c B抑制劑、脂質過氧化酶抑制劑、水-乙醢化-α -連結酸性二肽酶抑制劑、胰島素樣生長因子-I、血小板來源生長因子、血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉驗衍生物、尿核苷' 5 -經基-1 -甲基乙内醯脲、E_GB - 761、必莫克默、舒得塞、 Y - 1 2 8、止瀉劑 '瀉劑、羥曱基戊二醯輔酶A還原酶抑制劑、纖維酸衍生物、/5 3 -腎上腺素受體促效劑、醯基輔酶 A :膽固醇醯基轉移酶抑制劑、丙丁酚、甲狀腺受體促效劑、 312XP/發明說明書(補件)/94-07/94106583 26 ⑧ 1351400[3 2 ] The use of the condensed heterocyclic derivative or the pharmacological agent thereof according to any one of the above [1] to [9], wherein the medicinal composition for suppressing hyperglycemia after a meal is used, Academically acceptable salts or their prodrugs, and (B) selection of free insulin sensitivity enhancers, sugar absorption inhibitors 'biquinones, insulin secretion promoters, SGLT2 activity inhibitors, insulin or insulin analogues, glycosides Receptor antagonist, insulin receptor kinase stimulating agent, tripeptidase II inhibitor, dipeptidase IV inhibitor, protein tyrosine phosphatase 1 B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphate Enzyme inhibitor, fructose diphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic glucose stimulating inhibitor, D-hand inositol, glycogen synthase kinase-3 inhibitor, glycosidic peptide-1, Glycoglycan-like peptide-1 analog, glycoside-like peptide-1 agonist, fragrant tree, fragrant tree analog, auxin agonist, aldose reductase inhibitor, late glycation end Product formation inhibitor, protein kinase C inhibitor, 7-aminobutyric acid receptor antagonist Agent, sodium channel antagonist, transcription factor NF- /c B inhibitor, lipid peroxidase inhibitor, water-acetylated-α-linked acid dipeptidase inhibitor, insulin-like growth factor-I, platelet source Growth factors, platelet-derived growth factor analogs, epithelial growth factor, nerve growth factor, meat test derivatives, uridine nucleoside '5-trans-l-methylethyl carbazide, E_GB-761, 必莫克默, Shu Desai, Y - 1 2 8 , antidiarrheal agent laxative, hydroxypurin quinone quinone coenzyme A reductase inhibitor, fibric acid derivative, /5 3 -adrenergic receptor agonist, 醯Kievase A: cholesterol thiol transferase inhibitor, probucol, thyroid receptor agonist, 312XP / invention specification (supplement) /94-07/94106583 26 8 1351400

膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、肉鹼棕櫊醯基轉移酶抑制劑、鯊烯合成酶抑制劑、低比重脂蛋白受體增強劑、菸鹼酸衍生物、膽汁酸吸附劑、鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移蛋白抑制劑、食慾抑制劑 '血管升壓素轉移酶抑制劑、中性肽鍵内切酶抑制劑、血管升壓素I I 受體拮抗劑、内皮素轉移酶抑制劑' 内皮素受體拮抗劑、利尿劑、鈣離子拮抗劑' 血管擴張性降血壓劑、交感神經阻斷劑、中枢性降血壓劑、α 2 -腎上腺素受體促效劑、抗血小板劑、尿酸生成抑制劑、尿酸排泄促進劑及尿驗性化劑所構成群組中之至少1種藥劑。 [3 3 ] —種用於製造因高血糖症所引起疾病之預防或治療用醫藥組成物之藥劑之用途，係應用（A )上述[1 ]〜[9 ]中任一項中所記載之縮合雜環衍生物或其藥理學上所容許之鹽或其前驅藥，及（B )選擇自胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶到激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶 1 B 抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇、肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1 '升糖素樣胜肽-1類似物、升糖素樣胜肽-1 促效劑、香樹素、香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、後期糖化最終產物生 312XP/發明說明書(補件)/94-07/94106583 ⑧ 1351400 成抑制劑、蛋白質激酶C抑制劑、7 -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑、轉錄因子NF - /c B抑制劑、脂質過氧化酶抑制劑、介-乙醞化-α -連結酸性二肽酶抑制劑、胰島素樣生長因子-I、血小板來源生長因子、血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉驗衍生物、尿核苷、5 -經基-1 -曱基乙内酿腺、Cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthetase inhibitor, low specific gravity lipoprotein Receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium conjugated bile acid transfer factor inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant 'vasopressin transferase inhibitor, neutral peptide bond Endonuclease inhibitor, vasopressin II receptor antagonist, endothelin transferase inhibitor 'endothelin receptor antagonist, diuretic, calcium antagonist' vasodilator hypotensive agent, sympatholytic blocker At least one of the group consisting of a central hypotensive agent, an α 2 -adrenergic receptor agonist, an antiplatelet agent, a uric acid production inhibitor, a uric acid excretion promoter, and a urine test agent. [3 3 ] The use of a medicament for producing a pharmaceutical composition for prevention or treatment of a disease caused by hyperglycemia, wherein (A) any one of the above [1] to [9] is used a condensed heterocyclic derivative or a pharmacologically acceptable salt thereof or a prodrug thereof, and (B) selected from an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretion promoter, an SGLT2 activity inhibitor, insulin Or an insulin analogue, a glycoside receptor antagonist, an insulin receptor kinase to a agonist, a tripeptidase II inhibitor, a dipeptidase IV inhibitor, a protein tyrosine phosphatase 1 B inhibitor, glycogen phosphorylation Enzyme inhibitors, glucose-6-phosphatase inhibitors, fructose diphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic glycosity inhibitors, D-hand inositol, glycogen synthase kinase-3 inhibitors, Glycoglycan-like peptide-1 'glycoside-like peptide-1 analogue, glycoside-like peptide-1 agonist, fragrant tree, fragrant tree analog, auxin agonist, aldehyde Sugar reductase inhibitor, late glycation end product 312XP / invention manual (supplement) / 94 -07/94106583 8 1351400 inhibitors, protein kinase C inhibitors, 7-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- /c B inhibitors, lipid peroxidase inhibitors, Di-acetylated-α-linked acid dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epithelial growth factor, nerve growth factor, meat test derivative, urine nucleus Glycosides, 5-amino-pyridyl-1

E G Β - 7 6 1、必莫克默 '舒得塞、Υ - 1 2 8、止瀉劑、瀉劑、羥甲基戊二醯輔酶Α還原酶抑制劑 '纖維酸衍生物、/9 3 -腎上腺素受體促效劑、醯基輔酶 A :膽固醇醯基轉移酶抑制劑、丙丁酚、甲狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、肉鹼棕櫊醯基轉移酶抑制劑、鯊烯合成酶抑制劑、低比重脂蛋白受體增強劑、菸鹼酸衍生物、膽汁酸吸附劑 '鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移蛋白抑制劑、食慾抑制劑、血管升壓素轉移酶抑制劑、中性肽鏈内切酶抑制劑、血管升壓素I I受體拮抗劑、内皮素轉移酶抑制劑、内皮素受體拮抗劑、利尿劑、鈣離子拮抗劑、血管擴張性降血壓劑、交感神經阻斷劑、中樞性降血壓劑、α 2 -腎上腺素受體促效劑、抗血小板劑、尿酸生成抑制劑、尿酸排泄促進劑及尿驗性化劑所組成群組中之至少1種藥劑。 [3 4 ] —種用以製造阻止葡萄糖耐性異常者轉移為糖尿病之轉移阻止用醫藥組成物之用途，係應用（A )上述[1 ]〜[9 ] 中任一項所記載之縮合雜環衍生物或其藥理學上所容許之 28⑧ 312XP/發明說明書(補件)/94-〇7/94】06583 1351400EG Β - 7 6 1 , must Mokmer 'Sudse, Υ - 1 2 8, antidiarrheal, laxative, hydroxymethyl pentane quinone coenzyme Α reductase inhibitor 'fibrate derivative, / 9 3 - adrenergic receptor agonist, 醯Kymase A: cholesterol thiol transferase inhibitor, probucol, thyroid receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein Inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low specific gravity lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid adsorbents' sodium Yoke bile acid transfer factor inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, vasopressin transferase inhibitor, neutral endopeptidase inhibitor, vasopressin II receptor antagonist, endothelin Transferase inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilators, sympathomimetic blockers, central hypotensive agents, α 2 -adrenergic receptor agonists, Antiplatelet agent, uric acid production inhibitor, urine Urinary excretion promoter and agent of the experimental group at least one kind of a composition of matter. [3 4] The use of the condensed heterocyclic ring according to any one of the above [1] to [9], for use in the manufacture of a pharmaceutical composition for preventing metastasis to prevent diabetes from being metastasized to diabetes Derivative or its pharmacologically acceptable 288 312XP / invention specification (supplement) /94-〇7/94]06583 1351400

鹽或其前驅藥，及（B )選擇自胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑' SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶 1 B抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑 '丙酮酸去氫酶抑制劑、肝St新生抑制劑、D -手肌醇、肝酿合成酵素激酶-3抑制劑、升糖素樣胜肽-1、升糖素樣胜肽-1類似物、升糖素樣胜肽-1 促效劑、香樹素、香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、後期糖化最终產物生成抑制劑、蛋白質激酶C抑制劑、7 -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑、轉錄因子N F - λ: B抑制劑、脂質過氧化酶抑制劑、乙醯化-α -連結酸性二肽酶抑制劑、姨島素樣生長因子_ I、血小板來源生長因子、血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉鹼衍生物、尿核苷、5 -羥基-1 -甲基乙内醯脲、 E G Β - ? 6 1、必莫克默、舒得塞、Υ - 1 2 8、止瀉劑、瀉劑、羥甲基戊二醯輔酶Α還原酶抑制劑、纖維酸衍生物' yS 3 -腎上腺素受體促效劑、醯基輔酶 A :膽固醇醯基轉移酶抑制劑、丙丁酚、甲狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑 '微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、肉鹼棕櫚醯基轉移酶抑制劑、鯊烯合成酶抑制劑、低比重脂蛋白受體增強劑、菸鹼酸衍生物、膽汁酸吸附劑、鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移 312XP/發明說明書(補件)/94-07/94] 06583 29 ⑧a salt or a prodrug thereof, and (B) selected from an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretion promoter, an inhibitor of SGLT2 activity, an insulin or insulin analog, a glycoside receptor antagonist, Insulin receptor kinase stimulator, tripeptidase II inhibitor, dipeptidase IV inhibitor, protein tyrosine phosphatase 1 B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose The diphosphatase inhibitor 'pyruvate dehydrogenase inhibitor, liver St newborn inhibitor, D-hand inositol, hepatic enzyme synthase kinase-3 inhibitor, glycosidic peptide-1, glycoside-like victory Peptide-1 analog, glycoside-like peptide-1 agonist, fragrant tree, fragrant tree analog, auxin agonist, aldose reductase inhibitor, late glycation end product formation inhibitor, Protein kinase C inhibitor, 7-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-λ: B inhibitor, lipid peroxidase inhibitor, acetylated-α-linked acidic dipeptide Enzyme inhibitor, 姨-like growth factor _ I, platelet Source growth factor, platelet-derived growth factor analog, epithelial proliferation factor, nerve growth factor, carnitine derivative, urinary nucleoside, 5-hydroxy-1-methyl carbendazim, EG Β - ? 6 1 Kemer, Shudesai, Υ - 1 2 8, antidiarrheal, laxative, hydroxymethyl glutaraldehyde coenzyme Α reductase inhibitor, fibric acid derivative ' yS 3 - adrenergic receptor agonist, 醯Kiev enzyme A: cholesterol thiol transferase inhibitor, probucol, thyroid receptor agonist, cholesterol absorption inhibitor, lipase inhibitor 'microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, Carnitine palmitoyl transferase inhibitor, squalene synthetase inhibitor, low specific gravity lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium conjugated bile acid transfer factor inhibitor, cholesterol ester transfer 312XP/Invention Manual (supplement)/94-07/94] 06583 29 8

1351400 蛋白抑制劑、食慾抑制劑、血管升壓素轉移酶抑制劑性肽鏈内切酶抑制劑 '血管升壓素I I受體#抗劑、内轉移酶抑制劑、内皮素受體拮抗劑、利尿劑、鈣離子劑、血管擴張性降血壓劑 '交感神經阻斷劑、中框性壓劑、α 2 -腎上腺素受體促效劑、抗血小板劑 '尿酸抑制劑、尿酸排泄促進劑及尿鹼性化劑所組成群組中少1種藥劑。【實施方式】於本發明中，C，-6烷基為曱基 '乙基、丙基、異丙丁基、異丁基、第二丁基、第三丁基 '戊基、異戊基戊基、第三戊基、己基等碳原子數1〜6之直鏈狀或分烷基。Ci-6伸烷基或-C丨-6伸烷基-為亞曱基、伸乙基亞甲基、四亞甲基、伸丙基、1,1-二甲基伸乙基等碳數1〜6之直鏈狀或分枝狀伸烷基。-C! - 5伸烷基-為基、伸乙基、三亞甲基、四亞甲基 '伸丙基、1，1_二伸乙基等碳原子數1〜5之直鏈狀或分枝狀伸烷基。-伸烷基-為亞曱基' 伸乙基、三亞曱基、四亞曱基、基、1，1-二f基伸乙基等碳原子數1〜4之直鏈狀或狀伸烷基。羥（C 1 - 6烷）基為被羥基取代之上述C，- 6烷胺（C,-^烷）基為胺甲基、2-胺乙基等被胺基取代之 0-6烷基。氰（Ci-6烷）基為被氰基取代之上述Ci-6烷基曱醯（0-6烷）基為被胺曱醯基取代之上述1-6烷基。羧烷）基為被羧基取代之上述Ci-6烷基。 (：1-6烷氧基為曱氧基、乙氧基、丙氧基、異丙氧基、中皮素拮抗降血生成之至基、、新枝狀、三原子亞曱曱基 C 1 - 4 伸丙分枝基。上述。胺 (C 1 - 6 312XP/發明說明書(補件)/94-07/94 ] 06583 30 ⑧ 1351400 氧基、異丁氧基、第二丁氧基、第三丁氧基、戊氧基、異戊氧基、新戊氧基、第三戊氧基、己氧基等碳原子數1〜6 之直鏈狀或分枝狀烷氧基。羥（Ci-6烷氧）基為被羥基取代之上述（：卜6烷氧基。羧（Ci-6烷氧）基為被羧基取代之上述 Ci-6烷氧基。胺（Ci-6烷氧）基為被胺基取代之上述烷氧基。胺甲醯（Ci-6烷氧）基為被胺曱醯基取代之上述（：卜6烷氧基。C i - 6烷硫基為甲硫基、乙硫基、丙硫基、異丙硫基、丁硫基、異丁硫基、第二丁硫基、第三丁硫基、戊硫基、1351400 protein inhibitor, appetite suppressant, vasopressin transferase inhibitory endopeptidase inhibitor vasopressin II receptor #antibody, endotransferase inhibitor, endothelin receptor antagonist, Diuretic, calcium ion, vasodilator hypotensive agent 'sympathetic blocker, medium-frame pressure agent, α 2 -adrenergic receptor agonist, anti-platelet agent' uric acid inhibitor, uric acid excretion promoter and There is one less agent in the group consisting of urinary alkalizing agents. [Embodiment] In the present invention, C, -6 alkyl is decyl 'ethyl, propyl, isopropyl butyl, isobutyl, second butyl, tert-butyl 'pentyl, isoamyl pentyl A linear or a branched alkyl group having 1 to 6 carbon atoms such as a group, a third pentyl group or a hexyl group. Ci-6 alkyl or -C丨-6 alkyl - is a carbon number such as an anthracenylene group, an ethylidene group, a tetramethylene group, a propyl group, a 1,1-dimethylmethyl group A linear or branched alkyl group of 1 to 6 is alkyl. -C! - 5 alkyl or alkyl group, ethyl group, trimethylene group, tetramethylene group, propyl group, 1,1_diethylidene group, etc. Dendritic alkyl group. - an alkyl group - is an alkylidene group, an ethyl group, a trisylylene group, a tetramethylene group, a group, a 1,1-di-f-ethyl group, and the like, or a linear or alkyl group having 1 to 4 carbon atoms. . The hydroxy(C 1 - 6 alkyl) group is a C-6 alkyl group substituted by a hydroxyl group, and the C,-6 alkylamine (C,-alkyl) group is an amine methyl group, a 2-aminoethyl group or the like, which is substituted with an amine group. . The above-mentioned Ci-6 alkyl fluorene (0-6 alkyl) group having a cyanogen (Ci-6 alkylene) group substituted by a cyano group is the above 1-6 alkyl group substituted with an amine fluorenyl group. The carboxyalkyl) group is the above Ci-6 alkyl group substituted by a carboxyl group. (:1-6 alkoxy group is a decyloxy group, ethoxy group, propoxy group, isopropoxy group, mesothelin antagonistic to hypoxia-forming base, new branch, triatomic fluorenylene C 1 - 4 Extension of the branching group. The above. Amine (C 1 - 6 312XP / invention specification (supplement) / 94-07/94 ] 06583 30 8 1351400 oxy, isobutoxy, second butoxy, third a linear or branched alkoxy group having 1 to 6 carbon atoms such as butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, third pentyloxy group or hexyloxy group. Hydroxy (Ci- The 6 alkoxy) group is the above (: 6 alkoxy group substituted by a hydroxy group. The carboxy (Ci-6 alkoxy) group is the above Ci-6 alkoxy group substituted by a carboxyl group. An amine (Ci-6 alkoxy) group Is the above alkoxy group substituted by an amine group. The amine formamidine (Ci-6 alkoxy) group is the above substituted by an amine group (: a 6 alkoxy group. The C i 6 alkylthio group is a methylthio group) , ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, second butylthio, tert-butylthio, pentylthio,

異戊硫基、新戊硫基、第三戊硫基、己硫基等碳原子數 1 〜6之直鏈狀或分枝狀烷硫基。羥（C 1 - 6烷硫）基為被羥基取代之上述 C i - 6烷硫基。羧（C > - 6烷硫）基為被羧基取代之上述 C i 6烷疏基。胺（C，4烷硫）基為被胺基取代之上述 C! - s 烧硫基。 C2-6稀（alkenyl)基為乙稀基、稀丙基、1-丙稀基、異丙烯基、1- 丁烯基、2 - 丁烯基、2 -甲基烯丙基等碳原子數2〜6之直鏈狀或分枝狀烯基。C 2 - 6伸烯（a 1 k e n y 1 e n e )基或-C2-6伸烯基-為伸乙烯基、伸丙烯基等碳原子數2〜6 之直鏈狀或分枝狀伸烯基。-Cz-5伸烯基-為伸乙烯基、伸丙烯基等碳原子數 2〜5 之直鏈狀或分枝狀伸烯基。- 伸烯基-為伸乙烯基' 伸丙烯基等碳原子數 2 〜4之直鏈狀或分枝狀伸烯基。羥（C 2 - 6烯）基為被羥基取代之上述 C2-e烯基。羧（C2-6烯）基為被羧基取代之上述 C2-s 烯基。C2-6烯氧基為乙烯氧基、烯丙氧基、1-丙烯氧基、異丙烯氧基、1- 丁烯氧基、2 - 丁烯氧基、2 -甲基烯丙氧 312XP/發明說明書(補件)/94-07/94106583 31 1351400A linear or branched alkylthio group having 1 to 6 carbon atoms such as isopentylthio, neopentylthio, pentylthio and hexylthio. The hydroxy(C 1 - 6 alkylthio) group is the above-mentioned C i - 6 alkylthio group substituted by a hydroxy group. The carboxy (C > - 6 alkylthio) group is substituted by a carboxy group to form a C i 6 alkane group. The amine (C, 4 alkylthio) group is the above C!-s sulphur group substituted by an amine group. The C2-6 alkenyl group is a carbon atom such as an ethylene group, a dipropyl group, a 1-propyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group or a 2-methylallyl group. 2 to 6 linear or branched alkenyl groups. The C 2 - 6-alkylene (a 1 k e n y 1 e n e ) group or the -C 2-6-alkenyl group is a linear or branched alkenyl group having 2 to 6 carbon atoms such as a vinyl group or a propylene group. The -Cz-5-alkenyl group is a linear or branched alkyl group having 2 to 5 carbon atoms such as a vinyl group or a propylene group. - an alkenyl group - a linear or branched alkenyl group having 2 to 4 carbon atoms such as a vinyl group. The hydroxy (C 2 - 6 olefin) group is the above C2-e alkenyl group substituted by a hydroxy group. The carboxy (C2-6 olefin) group is the above C2-s alkenyl group substituted by a carboxyl group. C2-6 alkenyloxy is ethyleneoxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 2-methylallyloxy 312XP/ Invention description (supplement) /94-07/94106583 31 1351400

基等碳原子數2〜6之直鏈狀或分枝狀烯氧基。C2-6烯硫基為乙稀硫基、烤丙硫基、1 -丙稀硫基、異丙稀硫基、1 _ 丁烯硫基、2 - 丁烯硫基、2 -甲基烯丙硫基等碳原子數 2 〜6之直鏈狀或分枝狀烯硫基。C2-6炔（alkynyl)基為乙炔基、2 -丙炔基等碳原子數2〜6之直鏈狀或分枝狀C2-6炔基。- C2-6炔基-為伸乙炔基、伸丙炔基等碳原子數2〜6 之直鏈狀或分枝狀伸炔（alkynylene)基。-C2-5伸炔基-為伸乙炔基、伸丙炔基等碳原子數2〜5之直鏈狀或分枝狀伸炔基。-C2-4伸炔基-為伸乙炔基、伸丙炔基等碳原子數2〜4之直鏈狀或分枝狀伸炔基。單或二（C,-6烷）胺基為被上述Ci-6烷基單取代之胺基、或被同種或不同種上述 Ci-6烷基雙取代之胺基。單或二 (Ch烧)胺(Cn烧)基為被上述單或二(Cn烧)胺基取代之上述C,-6烷基。單或二（Cm烷）胺（Cm烷氧）基為被上述單或二（Ch烷）胺基取代之上述Cm烷氧基。單或二〔羥（Ch 烷）〕胺基為被上述羥（（：1-6烷）基單取代之胺基、或被任意之上述羥（C,-6烷）基雙取代之胺基。單或二（Ci-6烷）脲基為被上述Ci-6烷基單取代之脲基、或被任意之上述1-6烷基雙取代之脲基。單或二〔羥（0-6烷）〕脲基為被上述羥（Ci-6 烷）基單取代之脲基、或被任意之上述羥（Ci-6烷）基雙取代之脲基。單或二烷）磺醯胺基為被上述 C卜6烷基單取代之磺醯胺基、或被任意之上述C ! - C烷基雙取代之磺醯胺基。單或二〔羥（Ci-6烷）基〕磺醯胺基為被上述羥（Ci-6烷）基單取代之磺醯胺基、或被任意之上述羥（Ci-6烷）基雙取 312XP/發明說明書(補件)/94-07/94106583 32 ⑧ 1351400 代之磺醯胺基。c2-7 §s基為乙醯基、丙醯基、丁醯基、異丁醢基、戊醯基、三曱基乙醯基、己醯基等碳原子數2〜7 之直鏈狀或分枝狀醯基。Cm Si基胺基為被上述 Cm醯基取代之胺基。胺（Cz-7醒基胺）基為2 -胺基乙醯基胺基、3-胺基丙醯基胺基等被胺基取代之上述 C2-7醯基胺基。Ci-6 烷基亞磺醯基為曱基亞磺醯基、乙基亞磺醯基等碳原子數 1〜6之直鏈狀或分枝狀烷基亞磺醯基。C 1 - 6烷磺醯基為甲磺醯基、乙磺醯基等碳原子數〗〜6之直鏈狀或分枝狀烷磺A linear or branched alkenyloxy group having 2 to 6 carbon atoms and the like. C2-6 alkenylthio is ethylthio, roasted propylthio, 1-propylsulfanyl, isopropanylthio, 1 -butenylthio, 2-butenylthio, 2-methylallyl A linear or branched olefinic group having 2 to 6 carbon atoms such as a thio group. The C2-6 alkynyl group is a linear or branched C2-6 alkynyl group having 2 to 6 carbon atoms such as an ethynyl group or a 2-propynyl group. - C2-6 alkynyl- is a linear or branched alkynylene group having 2 to 6 carbon atoms such as an ethynyl group or a propargyl group. The -C2-5 alkynyl group is a linear or branched alkynyl group having 2 to 5 carbon atoms such as an ethynyl group or a propargyl group. The -C2-4 alkynyl group is a linear or branched alkynyl group having 2 to 4 carbon atoms such as an ethynyl group or a propargyl group. The mono- or di(C,-6-alkyl)amino group is an amine group monosubstituted by the above Ci-6 alkyl group, or an amine group which is disubstituted by the same or different kinds of the above Ci-6 alkyl group. The mono- or di-(Ch-) amine (Cn-sinter) group is the above-mentioned C, -6 alkyl group substituted by the above mono or di(Cn) amine group. The mono or di(Cm alkane)amine (Cm alkoxy) group is the above Cm alkoxy group substituted by the above mono or di(Ch alkyl)amine group. The mono- or bis[hydroxy(Ch)alkyl]amino group is an amine group monosubstituted by the above hydroxy ((:1-6 alkanyl) group or an amine group which is disubstituted by any of the above hydroxy (C, -6 alkane) groups The mono- or di(Ci-6 alkane)ureido group is a ureido group monosubstituted by the above Ci-6 alkyl group, or a ureido group which is disubstituted by any of the above 1-6 alkyl groups. Mono or di [hydroxyl (0- The 6-alkyl)]ureido group is a ureido group monosubstituted by the above hydroxy(Ci-6 alkane) group, or a ureido group which is disubstituted by any of the above hydroxy(Ci-6 alkane) groups. Mono or dialkyl) sulfonamide The group is a sulfonamide group which is monosubstituted by the above C 6 alkyl group, or a sulfonylamino group which is disubstituted by any of the above C?-C alkyl groups. The mono or bis[hydroxy(Ci-6)yl]sulfonylamino group is a sulfonylamino group monosubstituted by the above hydroxy(Ci-6 alkane) group, or an arbitrary hydroxy (Ci-6 alkylene) group Take 312XP / invention manual (supplement) /94-07/94106583 32 8 1351400 instead of sulfonamide. C2-7 §s is a linear or branched enthalpy of 2 to 7 carbon atoms such as acetamyl, propyl fluorenyl, butyl fluorenyl, isobutyl fluorenyl, amyl fluorenyl, trimethyl ethane fluorenyl and hexyl fluorenyl. base. The Cm Si-based amine group is an amine group substituted by the above Cm fluorenyl group. The amine (Cz-7 amide) group is the above C2-7 decylamino group substituted with an amine group such as a 2-aminoethylamino group or a 3-aminopropyl fluorenylamino group. The Ci-6 alkylsulfinyl group is a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms such as a fluorenylsulfinyl group or an ethylsulfinyl group. The C 1 - 6 alkanesulfonyl group is a linear or branched alkane having a carbon number of 〜6 or more such as a methylsulfonyl group or an ethylsulfonyl group.

醯基。C，- 6烷磺醯基胺基為被上述 C! - 6烷磺醯基取代之胺基。胺曱醯（C，- 6烷磺醯基胺）基為胺曱醯甲磺醯胺基等被胺甲醯基取代之上述 C丨-6烷磺醯基胺基。C丨-6烷磺醯基胺 (C丨-6烷）基為被上述 C丨-6烷磺醯基胺基取代之上述 Cl-6烷基。鹵素原子為氟原子、氣原子、溴原子或碘原子。鹵化（C , - 6 烷）基為被任意 1〜3個上述齒素原子取代之上述 Ci-6烷基。鹵化（C,-*!烷氧）基為被任意1〜3個上述鹵素原子取代之上述C，- 6烷氧基。函化（C，- 6烷硫）基為被任意1〜3個上述齒素原子取代之上述 Ci-6烷硫基。C2-7烷氧羰基為曱氧羰基、乙氧羰基、丙氧羰基、異丙氧羰基、丁氧羰基、異丁氧羰基、第二丁氧羰基、第三丁氧羰基、戊氧羰基、異戊氧羰基 '新戊氧羰基、第三戊氧羰基、己氧羰基等碳原子數2〜7之直鏈狀或分枝狀之烷氧羰基。C2-7烷氧羰（C,-6 烷）基為被上述C2-7烷氧羰基取代之上述Ci-C烷基。C2-7烷氧羰（C,-6烷氧）基為被上述 C卜7烷氧羰基取代之上述 Ci-6 33⑧ 312XP/發明說明書(補件)/94-〇7/ίΜ 106583 1351400 烷氧基。C2-7烷氧羰（Ci-6烷硫）基為被上述C2-7烷氧羰基取代之上述C I - 6院硫基。C 2 - 7烧氧幾（C 2 - 6稀）基為被上述C 2 - 7 烷氧羰基取代之上述Ci-6烯基。醯基. The C,-6 alkylsulfonylamino group is an amine group substituted by the above C!-6 alkanesulfonyl group. The amine hydrazine (C,-6 alkanesulfonylamine) group is the above-mentioned C丨-6 alkanesulfonylamino group substituted with an amine carbaryl group such as an amine sulfonylamino group. The C丨-6 alkanesulfonylamine (C丨-6 alkane) group is the above-mentioned Cl-6 alkyl group substituted by the above C丨-6 alkanesulfonylamino group. The halogen atom is a fluorine atom, a gas atom, a bromine atom or an iodine atom. The halogenated (C,-6 alkyl) group is the above-mentioned Ci-6 alkyl group substituted by any one of the above 1-3 dentate atoms. The halogenated (C, -*! alkoxy) group is the above C,-6 alkoxy group substituted by any 1 to 3 of the above halogen atoms. The functionalized (C,-6 alkylthio) group is the above-mentioned Ci-6 alkylthio group substituted by any one to three of the above dentate atoms. C2-7 alkoxycarbonyl is oxime oxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, second butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, iso A linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as a pentyloxycarbonyl group, a neopentyloxycarbonyl group, a third pentyloxycarbonyl group or a hexyloxycarbonyl group. The C2-7 alkoxycarbonyl (C, -6 alkyl) group is the above-mentioned Ci-C alkyl group substituted by the above C2-7 alkoxycarbonyl group. The C2-7 alkoxycarbonyl (C, -6 alkoxy) group is the above Ci-6 338 312XP/invention specification (supplement)/94-〇7/ίΜ 106583 1351400 alkoxylate substituted by the above C a 7 alkoxycarbonyl group base. The C2-7 alkoxycarbonyl (Ci-6 alkylthio) group is the above-mentioned C I - 6 thio group substituted by the above C 2-7 alkoxycarbonyl group. The C 2 - 7 alkoxy (C 2 - 6) group is the above Ci-6 alkenyl group substituted by the above C 2 - 7 alkoxycarbonyl group.

C3-7環烷基或C3_?環烷基-為環丙基、環丁基、環戊基、環己基、環庚基。C 3 - 7環烷（C , - 6烷）基為被上述C 3 - 7環烷基取代之上述Ci-6烷基。C3-7環烷（Cl-6烷氧）基為被上述C3-7 環烷基取代之上述C i · 6烷氧基。C 3 - 7環烷（C i - 6烷硫）基為被上述 C 3 - 7環烷基取代之上述 C i - 6烷硫基。C 3 - 7環烷氧基為被上述C 3 - 7環烷基取代之羥基。雜環烷基或雜環烷基-為由。末。林、硫代蛛。林、四氫呋喃、四氫哌喃、氮丙啶、一氮四圜、0比0各。定、°米。坐咬、11坐#、旅咬、0底D序、0比。坐。定、。比。各#、咪。坐淋等衍生之在結合部位以外之環内含有1〜2 個選擇自氧原子、硫原子及氮原子之任意雜原子之 3〜7 員環脂肪族雜環基，或由吲哚淋、異吲哚。林、四氫吲哚啉、四氫異。引β朵·#、六氫吲哚琳、六氫異吲°朵。林等衍生之在結合部位以外之環内含有1〜2個選擇自氧原子、硫原子及氮原子之任意雜原子之5或6員環與6員環縮合之脂肪族雜環基。雜環烷（C ! - 6烷）基為被上述雜環烷基取代之上述C , - 6 烷基。雜環烷（C，- 6烷氧）基為被上述雜環烷基取代之上述 C i - 6烷氧基。雜環烷（C , - 6烷硫）基為被上述雜環烷基取代之上述C I - 6烧硫基。 C6-I0芳基或C6-I。芳基-為苯基、奈基等碳原子數6或 10之芳香族環狀烴基。Cn»芳（Cm烷）基為被上述Ce-I。芳基取代之上述Cl-ϋ坑基。C6-I。芳（Cl-6烧氧）基為被上述C6-I0 312XP/發明說明書(補件)/9107/94〗〇6583 34 ⑧ 1351400 芳基取代之上述Cl-6烷氧基。Cfi-Ιβ芳（Cl-6烧硫）基為被上述C6-ID芳基取代之上述〇1-6烧硫基°C6-I。芳績酿基胺基為苯磺醯基胺基等之具有上述Cs-iO芳基之磺醯基胺基。Cuo 芳（C2-7烷氧羰）基為被上述（^-，。芳基取代之上述C2-7烷氧羰基。雜芳基或雜芳基-為由噻唑、4唑、異噻唑、異。号。坐、°比。定、0f咬、。比喷、。荅喷、°比°各、°塞吩、_ °坐、。比。坐、C3-7 cycloalkyl or C3_? cycloalkyl- is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The C 3 -7 cycloalkane (C , -6 alkane) group is the above Ci-6 alkyl group substituted by the above C 3 - 7 cycloalkyl group. The C3-7 cycloalkane (Cl-6 alkoxy) group is the above C i · 6 alkoxy group substituted by the above C3-7 cycloalkyl group. The C 3 -7 naphthenic (C i - 6 alkylthio) group is the above-mentioned C i - 6 alkylthio group substituted by the above C 3 - 7 cycloalkyl group. The C 3 -7 cycloalkoxy group is a hydroxyl group substituted by the above C 3 - 7 cycloalkyl group. Heterocycloalkyl or heterocycloalkyl- is. end. Lin, thio spider. Lin, tetrahydrofuran, tetrahydropyran, aziridine, mononitrogen tetramethylene, 0 to 0 each. Set, ° meters. Sitting bite, 11 sitting #, brigade bite, 0 bottom D order, 0 ratio. sit. Fixed, . ratio. Each #, microphone. The 3~7 member cycloaliphatic heterocyclic group containing 1 to 2 arbitrary hetero atoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in the ring other than the binding site derived from sitting or the like, or Hey. Lin, tetrahydroporphyrin, tetrahydroiso. Lead to β Duo·#, hexahydroindole, and hexahydroisoindole. The ring derived from the compound or the like contains 1 to 2 aliphatic heterocyclic groups in which a 5- or 6-membered ring condensed with a 6-membered ring is selected from any hetero atom of an oxygen atom, a sulfur atom and a nitrogen atom. The heterocycloalkane (C -6 -alkyl) group is the above C, - 6 alkyl group substituted by the above heterocycloalkyl group. The heterocycloalkane (C,-6 alkoxy) group is the above-mentioned C i - 6 alkoxy group substituted by the above heterocycloalkyl group. The heterocycloalkane (C,-6 alkylthio) group is the above-mentioned C I - 6 thiol group substituted by the above heterocycloalkyl group. C6-I0 aryl or C6-I. The aryl group is an aromatic cyclic hydrocarbon group having 6 or 10 carbon atoms such as a phenyl group or a naphthyl group. The Cn»aryl (Cm alkane) group is the above Ce-I. The above Cl-ϋ pit group substituted by an aryl group. C6-I. The aryl (Cl-6 alkoxy) group is the above Cl-6 alkoxy group substituted by the above C6-I0 312XP / invention specification (supplement) / 9107/94 〇 6583 34 8 1351400 aryl. The Cfi-Ιβ aryl (Cl-6 sulphur) group is the above 〇1-6 thiol group °C6-I substituted by the above C6-ID aryl group. The aromatic amine group is a sulfonylamino group having the above Cs-iO aryl group such as a phenylsulfonylamino group. The Cuo aryl (C2-7 alkoxycarbonyl) group is the above C2-7 alkoxycarbonyl group substituted by the above (^-, aryl group. Heteroaryl or heteroaryl group) is thiazole, 4 azole, isothiazole, iso No.. Sit, ° ratio. Fixed, 0f bite, than spray, 荅 spray, ° ° °, ° 塞, _ ° sit, than. Sit,

。等二。坐'。塞二。坐、四。坐、。夫咕等衍生之在結合部位以外之環内含有1〜4個選擇自氧原子 '硫原子及氮原子之任意雜原子之5員環或6員環芳香族雜環基，或由吲哚、異吲哚、苯并呋喃、異苯并呋喃、苯并噻吩、苯并噚唑 '苯并噻唑、。引。坐、苯并σ米°坐 '啥琳 '異01 #、。太D丼、啥琳、啥°坐你、。辛啉、吲畊、喹啶、喋啶等衍生之在結合部位以外之環内含有1〜4個選擇自氧原子、硫原子及氮原子之任意雜原子之5或6員環與6員環縮合之芳香族雜環基。雜芳（C】-6烷）基為被上述雜芳基取代之上述（：卜6烷基。雜芳（0-6烷氧）基為被上述雜芳基取代之上述〇^-6烷氧基。雜芳（Ci-6烷硫）基為被上述雜芳基取代之上述C，- 6烷硫基。脂環式胺基為N - °未琳基、硫代N -。末琳基、1 -氮丙咬基、 1 - 一氮四園基、1 - °比咯啶基、N -六氫吡啶基、1 -咪唑啶基、1 -哌畊基、四氫吡唑基等之在結合部位之氮原子以外可在環内具有1個選擇自氧原子、琉原子及氣原子之雜原子之5員環或6員環脂肪族環狀胺基。芳香族環狀胺基為 I -。米°坐基、1 - °比p各基、°比°坐基、1 -四。坐基等之在結合部位之氮*原子以外可在環内具有1〜3個Ιι原子之5員環芳香 35 312XP/發明說明書(補件)/94-07/94106583 1351400 族環狀胺基。芳香族環狀胺（C , - 6烷）基為被上述芳香族環狀胺基取代之上述Ci-6烷基。芳香族環狀胺（C 1-6烷氧）基為被上述芳香族環狀胺基取代之上述0-6烷氧基。芳香族環狀胺（C , - 6烷硫）基為被上述芳香族環狀胺基取代之上述 C I - 6烧硫基。. Wait two. sit'. Plug two. Sitting, four. sit,. a 5-membered ring or a 6-membered ring aromatic heterocyclic group derived from any ring of an oxygen atom 'sulfur atom and a nitrogen atom selected from a ring other than the bond site, or the like, derived from a ring other than the bond site, or Isoindole, benzofuran, isobenzofuran, benzothiophene, benzoxazole 'benzothiazole, . lead. Sitting, benzo and σ meters ° sit '啥琳' different 01 #,. Too D丼, 啥琳, 啥° sit on you. 5 or 6-membered rings and 6-membered rings containing 1-4 selected heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in the ring other than the binding site derived from octyl porphyrin, hydrazine, quinacrid, acridine or the like. A condensed aromatic heterocyclic group. The heteroaryl(C)-6-alkyl) group is the above-mentioned (:6-alkyl group. The heteroaryl (0-6 alkoxy) group is the above-mentioned oxime-6-substituted with the above heteroaryl group. The heteroaryl (Ci-6 alkylthio) group is the above C,-6 alkylthio group substituted by the above heteroaryl group. The alicyclic amine group is N - ° unlinedyl, thio N -. Base, 1-aziridine, 1-nitro-tetracyclyl, 1-cyromidyl, N-hexahydropyridyl, 1-imidazolidinyl, 1-piperidinyl, tetrahydropyrazolyl, etc. In addition to the nitrogen atom at the binding site, it may have a 5-membered ring or a 6-membered cyclic aliphatic amine group selected from a hetero atom of an oxygen atom, a halogen atom and a gas atom in the ring. The aromatic cyclic amine group is I-.m. sitting base, 1 - ° ratio p base, ° ratio ° sitting base, 1 - 4. Sitting base or the like at the binding site of nitrogen * atoms can have 1 to 3 Ιι atoms in the ring 5-member ring aromatic 35 312XP / invention specification (supplement) /94-07/94106583 1351400 cyclic amine group. The aromatic cyclic amine (C,-6 alkyl) group is substituted by the above aromatic cyclic amine group The above Ci-6 alkyl group. The aromatic cyclic amine (C 1-6 alkoxy) group is The substituent of the aromatic ring of the aromatic amine above cyclic amine 0-6 alkoxy (C, - 6 alkylthio). The above-described group is substituted with the above aromatic cyclic amino C I - 6 alkylthio burn.

羥基保護基為甲基、苄基 '甲氧甲基、乙醯基、三甲基乙醯基、苯醯基、第三丁基二曱基矽烷基' 第三丁基二笨基矽烷基、烯丙基等一般使用於有機合成反應之羥基保護基。胺基保護基為苄氧羰基、第三丁氧羰基、苄基、乙醞基、三氟乙醯基等一般使用於有機合成反應之胺基保護基。羧基保護基為甲基 '乙基、苄基、第三丁二曱基矽烷基、烯丙基等一般使用於有機合成反應之羧基保護基。又，於取代基Q中，左側鍵結部位表示與含氮縮合環之鍵結，右側鍵結部位表示與環A之鍵結。本發明之以上述一般式（I )表示之化合物，可依照下述方法及以該等為準之方法，或其他文獻所記載之方法及以該等為準之方法製造。 R3The hydroxy protecting group is methyl, benzyl 'methoxymethyl, ethyl fluorenyl, trimethyl ethinyl, phenyl fluorenyl, tert-butyl fluorenyl decyl 't-butyl bis- decyl fluorenyl, Allyl groups and the like are generally used for the hydroxy protecting group of the organic synthesis reaction. The amine protecting group is an amino group protecting group which is generally used in an organic synthesis reaction, such as a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, an ethyl fluorenyl group or a trifluoroethenyl group. The carboxy protecting group is a methyl 'ethyl group, a benzyl group, a tributyl decyl decyl group, an allyl group or the like which is generally used for a carboxyl group protecting group in an organic synthesis reaction. Further, in the substituent Q, the left bonding site indicates a bond with a nitrogen-containing condensed ring, and the right bonding site indicates a bond with the ring A. The compound represented by the above general formula (I) of the present invention can be produced by the following methods and methods based on the above, or the methods described in the other documents and the methods whichever are the same. R3

R2、步驟I r2 L2 L.'^~RV . 鋰化試劑 (π) ^^或 Mg 丄 1 rs_( λ (III) E2· Ε，·R2, step I r2 L2 L.'^~RV . Lithiation reagent (π) ^^ or Mg 丄 1 rs_( λ (III) E2· Ε, ·

MO'0' νΌΜ (Ga) 或MO'0' νΌΜ (Ga) or

MO 步驟 ⑴ 基化 (V) 還原 MO, R3MO Step (1) Base (V) Restore MO, R3

(IV) °-0 3 ] 2XP/發明說明書(補件)/94-07/94106583 36⑧ 1351400 [式中之£|3為氫原子、氟原子或苄氧基；EZa為氫原子、氟原子、甲基或苄氧甲基；L1為氯原子、溴原子或碘原子； L2為鋰原子、MgCl、MgBr或Mgl; Μ為苄基；G1為以式(IV) °-0 3 ] 2XP/Invention Manual (Supplement)/94-07/94106583 368 1351400 [In the formula, 3| is a hydrogen atom, a fluorine atom or a benzyloxy group; EZa is a hydrogen atom, a fluorine atom, Methyl or benzyloxymethyl; L1 is a chlorine atom, a bromine atom or an iodine atom; L2 is a lithium atom, MgCl, MgBr or Mgl; Μ is a benzyl group; G1 is a formula

或式Or

(式中M、Ela及Ε2°如同上述定義）表示之基；G2為羥基被苄基保護之上述G ; R1〜R6、G、Q、環A及環(wherein M, Ela and Ε2° are as defined above); G2 is the above G wherein the hydroxy group is protected by a benzyl group; R1 to R6, G, Q, ring A and ring

係如同上述定義。但在各化合物中存在羥基、胺基及/或羧基之情況，亦可適當使用具有保護基者。] 步驟1 將上述一般式（I I )表示之化合物，1 )在惰性溶劑中，使用正丁基鋰、第二丁基鋰、第三丁基鋰等鋰化試劑進行鋰化；或 2 )在惰性溶劑中，於碘、1，2 -二溴乙烷等添加劑之存在下，使用鎂調製格任亞試劑（Grignard’ s reagent);可藉以製造上述一般式（III)表示之化合物。使用於鋰化反應之溶劑，可列舉如四氫呋喃、二乙醚及該等之混合溶劑等，反應溫度通常為-1 0 0〜〇 °C，反應時間因所 37 312XP/發明說明書(補件)m-07/941065幻 1351400It is as defined above. However, in the case where a hydroxyl group, an amine group and/or a carboxyl group are present in each compound, those having a protective group may be suitably used. Step 1: The compound represented by the above general formula (II), 1) is lithiated in an inert solvent using a lithiating reagent such as n-butyllithium, t-butyllithium or t-butyllithium; or 2) In an inert solvent, a magnesium-modified Grignard's reagent is used in the presence of an additive such as iodine or 1,2-dibromoethane; and the compound represented by the above general formula (III) can be produced. The solvent used for the lithiation reaction may, for example, be tetrahydrofuran, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually -1 0 0 to 〇 ° C, and the reaction time is 37 312 XP / invention specification (supplement) m -07/941065 fantasy 1351400

使用之原料物質或溶劑、反應溫度等而異，但通常為1分鐘〜3 小時。使用於格任亞試劑之調製的溶劑可列舉如四氫呋喃、二乙醚及該等之混合溶劑等，反應溫度通常為〇°c 〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為3 0分鐘〜5小時。步驟2 將上述一般式（III)表示之化合物與上述一般式（Ga)或 (G b )表示之糖内酯，在惰性溶劑中進行縮合，可藉以製造上述一般式（I V )表示之化合物。所使用之溶劑可列舉如四氫呋喃、二乙醚及該等之混合溶劑等，反應溫度通常為 -1 0 0 °C〜室溫，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為5分鐘〜5小時。步驟3 將上述一般式（I V )表示之化合物，在惰性溶劑中，於三氟化硼•二乙醚錯合物之存在下，使用三乙基矽烷、三異丙基矽烷等試劑進行還原，脫去變旋異構（a η 〇 m e r )位之羥基，可藉以製造上述一般式（V )表示之化合物。所使用之溶劑可列舉如乙腈、氣化甲烷、1，2 -二氣乙烷及該等之混合溶劑等。反應溫度通常為-20 °C〜室溫，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為3 0分鐘〜 1曰° 步驟4 將上述一般式（V )表示之化合物，1 )在惰性溶劑中，使用鈀碳粉末等鈀系觸媒進行接觸還原；或 2 )在惰性溶劑 ⑧ 312XP/發明說明書(補件)/94-07/94〗06583 1351400The raw material or solvent to be used, the reaction temperature, etc. vary, but usually it is 1 minute to 3 hours. The solvent to be used in the preparation of the reagent can be, for example, tetrahydrofuran, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually 〇°c to reflux temperature, and the reaction time depends on the raw material or solvent used, the reaction temperature, and the like. Different, but usually 30 minutes to 5 hours. Step 2 A compound represented by the above formula (IV) can be produced by condensing a compound represented by the above formula (III) with a sugar lactone represented by the above general formula (Ga) or (G b ) in an inert solvent. The solvent to be used may, for example, be tetrahydrofuran, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually -1 to 0 ° C to room temperature, and the reaction time varies depending on the raw material or solvent to be used, the reaction temperature, and the like. But usually it is 5 minutes to 5 hours. Step 3: The compound represented by the above general formula (IV) is reduced in an inert solvent in the presence of a boron trifluoride diethyl ether complex using a reagent such as triethyl decane or triisopropyl decane. The compound represented by the above general formula (V) can be produced by deactivating the hydroxyl group at the a η 〇mer position. The solvent to be used may, for example, be acetonitrile, vaporized methane, 1,2-dioxaethane or the like. The reaction temperature is usually -20 ° C to room temperature, and the reaction time varies depending on the raw material or solvent to be used, the reaction temperature, etc., but is usually 30 minutes to 1 Torr. Step 4 The above general formula (V) is represented. a compound, 1) in a noble solvent, using a palladium-based catalyst such as palladium carbon powder for contact reduction; or 2) in an inert solvent 8 312XP / invention specification (supplement) /94-07/94〗06583 1351400

中，於三氟化硼•二乙鲮錯合物等酸之存在下進行處理’ 脫去苄基，可藉以製造本發明之上述一般式（I)表示之化合物。揍觸還原所使用之溶劑可列舉如甲醇、乙醇、醋酸乙 S旨、四氫呋喃、醋酸及該等之混合溶劑，反應溫度通常為 o°c〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1小時〜2日。酸處理所使用之溶劑可列舉如氣化曱烷、1 , 2 -二氣乙烷、乙腈及該等之混合溶劑等，反應溫度通常為 0 °C〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為30 分鐘〜1日。本發明之上述一般式（I)表示之化合物中，Q為-Ci-6伸坑基-、-C2-6伸烤基-、-〇2-6伸炔基-、- Cl - 6伸统基-〇_ 、-(]丨-6伸院基-5_ 、_0丨-6伸院基-〇_(^丨-6伸坑基-或-Cl-6伸烧基-S - Cl-6伸炫基_之苯并11夫喃化合物，亦可依上述方法為準，使用可由下述化合物（V I )In the present invention, the compound represented by the above general formula (I) of the present invention can be produced by subjecting it to treatment in the presence of an acid such as boron trifluoride or diethylidene complex. The solvent used for the reduction can be exemplified by methanol, ethanol, acetic acid, tetrahydrofuran, acetic acid, and the like. The reaction temperature is usually from o ° c to reflux temperature, and the reaction time is due to the raw material or solvent used. The reaction temperature varies, but is usually from 1 hour to 2 days. The solvent used for the acid treatment may, for example, be gasified decane, 1,2-diethane, acetonitrile or a mixed solvent thereof, and the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is due to the raw materials used. The substance or solvent, reaction temperature, etc. vary, but usually 30 minutes to 1 day. In the compound of the above general formula (I) of the present invention, Q is -Ci-6 exfoliation-, -C2-6 exocyclic-, -〇2-6-alkynyl-, -Cl-6 exud基-〇_,-(]丨-6伸院基-5_,_0丨-6伸院基-〇_(^丨-6伸坑基- or -Cl-6 stretching base-S-Cl-6 The benzoheptane compound of the present invention can also be used according to the above method, and the following compound (VI) can be used.

och3 (VI) 製造之下述化合物（VII)，依下述步驟5〜10製造。The following compound (VII) manufactured by och3 (VI) was produced in the following steps 5 to 10.

312XP/發明說明書(補件)/94-07/94】06583 1351400 (式中之RID為甲基或乙基；G3為羥基被乙醯基、三曱基乙醢基、笨曱醢基等醯基保護之上述 G ; L3為氣原子或溴原子；Q1為- Cl - 6伸烧基-、-Cz'6伸烤基-、_C2-6伸块312XP/Inventive Manual (Supplement)/94-07/94]06583 1351400 (wherein RID is methyl or ethyl; G3 is hydroxyl group is acetyl group, trimethyl ethane group, awkward group, etc.) The above-mentioned G of the base protection; L3 is a gas atom or a bromine atom; Q1 is a -Cl-6 extension base-, -Cz'6 extension base-, _C2-6 extension block

基 - - C〗 -6 \ 炫基 -0 、 - c. -6 伸：院基 S - 、 — C 1-6 伸烷基 ~ 0 -1 C.- 6 伸烷基 - 或 - C丨 '6 伸 L基- S - C.· .6 伸烷基 - ; R丨 R3 、1 R5 ' R6 ' G 及環 A 如同上述定義〇但於各化合物中存在羥基、胺基及 /或羧基之情況，亦可適當使用具有保護基者〇 ) 步驟 5 將上述 — 般式（VI I )表示之4匕合物在惰性溶劑中 j 於 0比啶、三乙胺 N, N - 二異丙基乙胺等驗之存在 .下，在 4 - 二曱基胺基 °tb 啶等添加劑之存在或不存在下使用氯化乙醯氣化二甲基乙醞氣化苯甲醯等醯基化劑進行 0 丨醯基化 9 可藉以製造上述 — 般式 (V I ] ! I ) 表示之化合物 0 反應所使用之溶劑可列 1舉如 0比。定三乙胺、 ' N, N - 二異丙基乙胺 X 氣化曱烷、 1， 2 - 二氯乙烧，氫口夫 :喃、乙腈、醋酸乙酯及該等之混合溶劑等。反應溫度通常為 0' 3C 回流溫度反應時間因所使用之原料物質或溶劑 > 反應温度等而異但通常為 1 小時 5 曰〇步驟 6 將上述 — 般式 ( VI . I I ) 表 .示之化合物 5 在惰性溶劑中 » 於氣化鋁等之路易士 (Lew i s )酸之存在下 j 使用上述一般式 (I X) 表示之化合物進行 F re i d e ：1 - C r ε if t S 反應予以醯基化及脫甲基化 5 可藉以製造上述- — 般式 (X )表示之化合物〇 312XP/發明說明書(補件)/94-07/94106583Base - - C〗 -6 \ 炫基-0, - c. -6 Extension: Dean S - , - C 1-6 alkylene ~ 0 -1 C.- 6 alkyl - or - C丨' 6 Extension L-S-C.·.6 alkylene-; R丨R3, 1 R5 'R6 'G and ring A are as defined above, but the presence of hydroxyl, amine and/or carboxyl groups in each compound , which can also be suitably used as a protecting group.) Step 5 The above 4-formed compound represented by the general formula (VI I ) is in an inert solvent, and is added to 0-pyridine, triethylamine N, N-diisopropyl B. In the presence or absence of an amine, etc., in the presence or absence of an additive such as 4-dimercaptoamine-based tbb pyridine, the thiolating agent such as benzyl hydrazine gasification of dimethyl hydrazine is gasified with acetonitrile. 0 The thiolation 9 can be used to produce the above-mentioned compound (VI) ! I). The solvent used for the reaction of the compound 0 can be listed as a ratio of 0. Triethylamine, 'N, N-diisopropylethylamine X gasified decane, 1,2-dichloroethane, hydrogen mouth: methane, acetonitrile, ethyl acetate, and the like. The reaction temperature is usually 0' 3C. The reflux temperature reaction time varies depending on the starting material or solvent used, the reaction temperature, etc., but is usually 1 hour 5 曰〇 Step 6 The above-mentioned general formula (VI. II) is shown. Compound 5 is dissolved in an inert solvent in the presence of a Lewis acid such as vaporized aluminum. The compound represented by the above general formula (IX) is subjected to F re ide :1 - C r ε if t S reaction. Basement and demethylation 5 can be used to produce the compound represented by the above formula (X) 〇 312XP / invention specification (supplement) /94-07/94106583

1351400 所使用之溶劑可列舉如氣化甲烷、1，2 -二氣乙烷、二硫碳、氣苯及該等之混合溶劑等，反應溫度通常為〇°C〜流溫度，反應時間因所使用之原料物質或溶劑、反應溫等而異，但通常為1小時〜5小時。步驟7 將上述一般式（X)表示之化合物，在惰性溶劑中，於酸鉀、碳酸鉋等鹼之存在下，使用上述一般式（XI)表示鹵化醋酸I旨進行-烧基化，可藉以製造上述一般式（X I 表示之化合物。所使用之溶劑可列舉如 I yV -二曱基甲胺、丙酮及該等之混合溶劑等。反應溫度通常為室溫〜流溫度，反應時間因所使用之原料物質或溶劑、反應溫等而異，但通常為1小時〜5曰。步驟8 將上述一般式（XII)表示之化合物，於氫氧化鈉、氫化鉀等鹼性物質之存在下進行水解，可藉以製造上述一式（X I I I )表示之苯氧基醋酸衍生物。所使用溶劑可列舉曱醇、乙醇、2 -丙醇、四氫呋喃、水及該等之混合溶劑等反應溫度通常為室溫〜回流溫度，反應時間因所使用之料物質或溶劑、反應溫度等而異，但通常為1小時〜1曰步驟9 將上述一般式（X I I I )表示之化合物，在惰性溶劑中，醋酸鈉及醋酸酐之存在下進行環化，可藉以製造上述一式（V a )表示之苯并呋喃衍生物。所使用溶劑可列舉如酸，反應溫度通常為5 0 t〜回流溫度，反應時間因所使化回度碳之 I ) 醯回度氧般如 > 原〇於般醋用 312XP/發明說明書(補件)/94-07/94106583 41 ⑧Examples of the solvent used in 1351400 include gasified methane, 1,2-dioxaethane, disulfide carbon, gas benzene, and the like. The reaction temperature is usually 〇 ° C to flow temperature, and the reaction time is The raw material or solvent to be used, the reaction temperature, and the like may vary, but it is usually from 1 hour to 5 hours. Step 7 The compound represented by the above general formula (X) can be subjected to alkylation in an inert solvent in the presence of a base such as potassium acid or carbonic acid, and the above-mentioned general formula (XI) is used to represent the halogenated acetic acid. The compound represented by the above general formula (XI) is produced. The solvent to be used may, for example, be yV-dimercaptomethylamine, acetone or a mixed solvent thereof, etc. The reaction temperature is usually room temperature to flow temperature, and the reaction time is used. The raw material or solvent, the reaction temperature, and the like may be different, but it is usually 1 hour to 5 Torr. Step 8 The compound represented by the above general formula (XII) is hydrolyzed in the presence of a basic substance such as sodium hydroxide or potassium hydride. The phenoxyacetic acid derivative represented by the above formula (XIII) can be produced. The solvent to be used is decyl alcohol, ethanol, 2-propanol, tetrahydrofuran, water, and the like, and the reaction temperature is usually room temperature. The reflux temperature and the reaction time vary depending on the materials or solvents used, the reaction temperature, etc., but usually 1 hour to 1 Torr. Step 9 The compound represented by the above general formula (XIII) is dissolved in an inert solution. The cyclization is carried out in the presence of sodium acetate and acetic anhydride to produce a benzofuran derivative represented by the above formula (V a ). The solvent used may, for example, be an acid, and the reaction temperature is usually 50 t to reflux temperature. The reaction time is due to the degree of carbonization of the carbon. I) is like oxygen. As it is used in vinegar, 312XP/invention specification (supplement)/94-07/94106583 41 8

1351400 之原料物質或溶劑、反應溫度等而異，但通常為1小曰° 步驟1 0 將上述一般式（Va)表示之化合物’於氫氧化鈉、鈉、乙醇鈉等鹼性物質之存在下進行水解，可藉以製述一般式（I a )表示之化合物。所使用溶劑可列舉如曱乙醇、四氫呋喃、水及該等之混合溶劑等，反應溫度為 0 °C〜回流溫度，反應時間因所使用之原料物質劑、反應溫度等而異’但通常為3 0分鐘〜1曰。上述製造方法之起始原料可依文獻記載之方法或等為準之方法等製造。又，上述一般式（II)表示之化中，以下述一般式（IIa)、（IIb)或（lie)表示之化合物依下述步驟11〜17製造。甲醇造上醇、通常或溶以其合物亦可1351400 varies depending on the starting material or solvent, reaction temperature, etc., but is usually 1 hour. Step 1 0 The compound represented by the above general formula (Va) is present in the presence of an alkaline substance such as sodium hydroxide, sodium or sodium ethoxide. Hydrolysis can be carried out to prepare a compound represented by the general formula (I a ). The solvent to be used may, for example, be hydrazine ethanol, tetrahydrofuran, water or a mixed solvent thereof, and the reaction temperature is from 0 ° C to reflux temperature, and the reaction time varies depending on the raw material substance to be used, the reaction temperature, etc., but usually 3 0 minutes ~ 1曰. The starting materials of the above production methods can be produced by a method or the like as described in the literature. Further, in the above formula (II), the compound represented by the following general formula (IIa), (IIb) or (lie) is produced in the following steps 11 to 17. Methanol can be made from alcohol, usually or dissolved.

312XP/發明說明書(補件)/94-07/94】06583 42 1351400 (式中之A3為氧原子、硫原子或與R9鍵結之氮原子；L4為鋰原子、MgCl、MgBr 或 Mgl ; L5 為-P(=0)(0Ru)2 或-P + (PPh3)3X— ; R11為Cu烷基；Ph為苯基；X為氣原子、溴原子或碘原子；Q2為單鍵、- Cm伸烷基-、- C2-5伸烯基-' - C2-5伸快基-、-C丨-5伸烧基_0_ ' _Cl-5伸烧基-S- 、 - Cl-5伸烧基-〇 - Cl-6伸院基_或-Cl-5伸烧基- S-C丨-6伸烷基-;Q3為單鍵、-C丨--伸烷基-' -Ch312XP/Invention Manual (Supplement)/94-07/94]06583 42 1351400 (wherein A3 is an oxygen atom, a sulfur atom or a nitrogen atom bonded to R9; L4 is a lithium atom, MgCl, MgBr or Mgl; L5 Is -P(=0)(0Ru)2 or -P+(PPh3)3X-; R11 is Cu alkyl; Ph is phenyl; X is a gas atom, a bromine atom or an iodine atom; Q2 is a single bond, -Cm Alkyl-, -C2-5-extended alkenyl-'-C2-5 extended fast--, -C丨-5 extended alkyl group____Cl-5 extended alkyl-S-, -Cl-5 extended burning 〇-〇-Cl-6 stretching base _ or -Cl-5 stretching alkyl group - SC丨-6 alkylene group-; Q3 is a single bond, -C丨--alkylene-'-Ch

伸稀基-、-〇2-4伸快基-'-〇丨-4伸炫<基-〇-、_0丨-4 伸炫I基- S- 、 -〇1-4伸烧基-〇-(3)-6伸炫1基-或_0丨-4伸烷基-S - C,-6伸烷基-;R1〜R6、R9、L1及環 A如同上述定義。）步驟1 1 將上述一般式（X I V )表示之化合物，在惰性溶劑中，於氣化鋁等之路易士酸存在下，使用上述一般式（XV)表示之化合物進行Freidel - Crafts反應而醯基化，可藉以製造上述一般式（X V I )表示之化合物。所使用溶劑可列舉如氯化甲烷、1 , 2 -二氣乙烷、二硫化碳、該等之混合溶劑等，反應溫度通常為 0 °C〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為3 0分鐘〜1曰。步驟1 2 將上述一般式（X V I )表示之化合物，在惰性溶劑中，於三氟醋酸等酸之存在下，使用三乙基矽烷等試劑進行還原，可藉以製造上述一般式（1 I a )表示之化合物。所使用溶劑可列舉如三氟醋酸、氯化曱烷、1，2 -二氣乙烷及該等之 312XP/發明說明書(補件)/94-07/94106583Stretching base -, -〇2-4 stretching fast base - '-〇丨-4 stretching dazzle <基-〇-,_0丨-4 伸炫 I base - S-, -〇1-4 stretching base - 〇-(3)-6 stretching 1 base- or _0丨-4 alkyl-S-C,-6-alkyl-; R1 to R6, R9, L1 and ring A are as defined above. Step 1 1 The compound represented by the above general formula (XIV) is subjected to a Freidel-Crafts reaction using a compound represented by the above general formula (XV) in the presence of a Lewis acid such as vaporized aluminum in an inert solvent. The compound represented by the above general formula (XVI) can be produced. The solvent to be used may, for example, be chlorinated methane, 1,2-diethane, carbon disulfide, or a mixed solvent thereof, and the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is due to the raw material or solvent used. The reaction temperature varies, but is usually from 30 minutes to 1 Torr. Step 1 2 The above general formula (1 I a ) can be produced by reducing the compound represented by the above formula (XVI) in an inert solvent in the presence of an acid such as trifluoroacetic acid using a reagent such as triethylsulfane. Expressed as a compound. The solvent to be used may, for example, be trifluoroacetic acid, decane chloride, 1,2-diethane, and the like (312) / invention specification (supplement) /94-07/94106583

1351400 混合溶劑等，反應溫度通常為〇 °c〜回流溫度，反應因所使用之原料物質或溶劑、反應溫度等而異，但通 30分鐘〜3日。步驟1 3 將上述一般式（X I V )表示之化合物，在惰性溶劑中用氣氧化磷及介，水-二甲基甲醯胺進行Vilsmeier反可藉以製造上述一般式（XVII)表示之化合物。使用於之溶劑可列舉如 I # -二曱基甲醯胺、乙腈、氯化甲 1，2 -二氣乙烷及該等之混合溶劑等，反應溫度通常為〜回流溫度，反應時間因所使用之原料物質或溶劑、溫度等而異，但通常為3 0分鐘〜1日。步驟1 4 將上述一般式（X V I I )表示之化合物，使用以上述一 (X V I I I )表示之有機鋰試劑或格任亞試劑進行縮合，可上述一般式（X I X )表示之化合物。所使用溶劑可列舉如呋喃、二乙醚及該等之混合溶劑等，反應溫度通常為-〜室溫，反應時間因所使用之原料物質或溶劑、反應等而異，但通常為30分鐘〜1曰。步驟1 5 將上述一般式（X I X )表示之化合物，1 )在惰性溶劑於二甲基胺基吡啶之存在下，使用硼烷•四氫錯合物、硼烷•二曱基硫化物錯合物等硼烷試劑進原；或2)在惰性溶劑中，於三氟醋酸、三氟化硼•二錯合物等酸之存在下，使用三乙基矽烷等試劑進行還時間常為，使應，反應烷、 or 反應般式製-造四氫 7 8 °C 溫度中，呋喃行還乙醚原； 3】2XP/發明說明書(補件)/94-0刀94 ] 065 83 ⑧1351400 Mixed solvent, etc., the reaction temperature is usually 〇 °c ~ reflux temperature, the reaction varies depending on the raw material or solvent used, the reaction temperature, etc., but it takes 30 minutes to 3 days. Step 1 3 The compound represented by the above general formula (X I V ) is subjected to Vilsmeier reaction using phosphorus oxyhydroxide and water-dimethylformamide in an inert solvent to produce a compound represented by the above general formula (XVII). The solvent to be used may, for example, be I #-dimercaptomethylamine, acetonitrile, methyl 1,2-diethane, and the like, and the reaction temperature is usually - reflux temperature, and the reaction time is The raw material or solvent used, temperature, etc. vary, but usually 30 minutes to 1 day. Step 1 4 The compound represented by the above formula (X V I I ) can be condensed by using the organolithium reagent or the genomic reagent represented by the above-mentioned (X V I I I ), and the compound represented by the above formula (X I X ) can be used. The solvent to be used may, for example, be furan, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually -2 room temperature, and the reaction time varies depending on the starting material or solvent used, reaction, etc., but usually 30 minutes to 1 Hey. Step 1 5 The compound represented by the above general formula (XIX), 1) in the presence of an inert solvent in the presence of dimethylaminopyridine, using a borane-tetrahydro complex, a borane-didecyl sulfide The borane reagent such as a substance is introduced into the original; or 2) in an inert solvent, in the presence of an acid such as trifluoroacetic acid, boron trifluoride or a di-de complex, using a reagent such as triethyl decane, the time is often Should, the reaction of alkane, or reaction-like system - tetrahydrogen 7 8 ° C temperature, furan also ether original; 3] 2XP / invention manual (supplement) / 94-0 knife 94 ] 065 83 8

1351400 可藉以製造上述一般式（I丨a)表示之化合物。於還原使用之溶劑，可列舉如四氫呋喃、二乙醚及該等之混劑等，反應溫度通常為 0°C〜回流溫度，反應時間因用之原料物質或溶劑、反應溫度等而異，但通常為30 〜5日。於還原2 )所使用之溶劑可列舉如三氟醋酸、曱烷、1 , 2 -二氣乙烷及該等之混合溶劑等，反應溫度為 0°C〜回流溫度，反應時間因所使用之原料物質劑、反應溫度等而異，但通常為3 0分鐘〜5曰。步驟16 將上述一般式（X V I I )表示之化合物，在惰性溶劑中氫化鈉、氫氧化鈉、第三丁醇鉀、正丁基鋰、第三丁等鹼之存在下，使用上述一般式（XX)表示之化合物 Wittig反應或Horner - Emmons反應，可藉以製造上般式（I I b )表示之化合物。反應所使用之溶劑可列舉如呋喃、/V, yV-二曱基曱醯胺、二甲基亞颯、曱醇、乙醇腈、水及該等之混合溶劑等，反應溫度通常為 0 °C〜溫度，反應時間因所使用之原料物質或溶劑、反應溫而異，但通常為30分鐘〜1日。步驟1 7 將上述一般式（1 I b )表示之化合物，1 )在惰性溶劑使用鈀碳粉末等鈀系觸媒進行接觸還原；或2 )在惰性中，於三乙胺、/V, /V-二異丙基乙胺等鹼之存在或不下，使用 2,4,6-三異丙基苯磺醞肼等試劑進行二醖還原，可藉以製造上述一般式（I I c )表示之化合物。接 3 ] 2XP/發明說明書(補件)/94-07/94106583 I )所合溶所使分鐘氣化通常或溶，於基鋰進行述一四氫、乙回流度等中，溶劑存在亞胺觸還 45 1351400 原所使用之溶劑可列舉如曱醇、乙醇、醋酸乙酯、四氫呋喃、醋酸及該等之混合溶劑等。反應溫度通常為〇 °c〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1小時〜2日。二醯亞胺還原所使用之溶劑可列舉如四氫呋喃、二乙醚及該等之混合溶劑等，反應溫度通常為室溫〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1小時〜3曰。1351400 can be used to produce the compound represented by the above general formula (I丨a). The solvent to be used for the reduction may, for example, be tetrahydrofuran, diethyl ether or a mixture thereof, and the reaction temperature is usually from 0 ° C to the reflux temperature, and the reaction time varies depending on the starting material or solvent used, the reaction temperature, etc., but usually For 30 to 5 days. The solvent to be used for the reduction 2) may, for example, be trifluoroacetic acid, decane, 1,2-diethane, or a mixed solvent thereof, and the reaction temperature is from 0 ° C to the reflux temperature, and the reaction time is used. The raw material agent, the reaction temperature, and the like may vary, but it is usually from 30 minutes to 5 Torr. Step 16 The compound represented by the above general formula (XVII) is used in the presence of a base such as sodium hydride, sodium hydroxide, potassium butoxide, n-butyllithium or tert-butyl in an inert solvent, and the above general formula (XX) is used. The compound represented by the Wittig reaction or the Horner-Emmons reaction can be used to produce a compound represented by the above formula (II b ). The solvent to be used in the reaction may, for example, be furan, /V, yV-didecylguanamine, dimethyl hydrazine, decyl alcohol, glycolonitrile, water, and the like, and the reaction temperature is usually 0 ° C. ~ Temperature, reaction time varies depending on the starting material or solvent used, and the reaction temperature, but it is usually 30 minutes to 1 day. Step 1 7 The compound represented by the above general formula (1 I b ), 1) is contact-reduced with a palladium-based catalyst such as palladium carbon powder in an inert solvent; or 2) in an inert state at triethylamine, /V, And the presence or absence of a base such as /V-diisopropylethylamine, and the reduction of dioxime using a reagent such as 2,4,6-triisopropylbenzenesulfonate, whereby the above general formula (II c ) can be produced. Compound. 3] 2XP / invention manual (supplement) /94-07/94106583 I) The solution is dissolved in a minute or a solution, in the case of lithium, the tetrahydrogen, ethyl reflux, etc. The solvent to be used for the above-mentioned 45 135 1400 may, for example, be decyl alcohol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid or a mixed solvent thereof. The reaction temperature is usually 〇 °c to reflux temperature, and the reaction time varies depending on the raw material or solvent to be used, the reaction temperature, etc., but it is usually from 1 hour to 2 days. The solvent used for the reduction of the quinone imine may, for example, be tetrahydrofuran, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually room temperature to reflux temperature, and the reaction time varies depending on the raw material or solvent used, the reaction temperature, and the like. But usually for 1 hour ~ 3 baht.

上述一般式（XIV)表示之化合物中，A3為硫原子之化合物，亦可依下述步驟18及19製造。Among the compounds represented by the above general formula (XIV), a compound wherein A3 is a sulfur atom can also be produced by the following steps 18 and 19.

(XXI) ra 〇Rw (XXII) OR1· SH 步驟 18 r2-(XXI) ra 〇Rw (XXII) OR1· SH Step 18 r2-

OR12 R3 0R» 步驟 19r2- (XXIII) 環化OR12 R3 0R» Step 19r2- (XXIII) Cyclization

(XlVa)(XlVa)

(式中之L6為氣原子、溴原子或碘原子；R12為甲基或乙基，或兩者鍵結形成伸乙基或三亞曱基；R1〜R4及L1如同上述定義。）步驟1 8 將上述一般式（X X I )表示之化合物，在惰性溶劑中，於碳酸鉀、碳酸鉋、三乙胺、I介-二異丙基乙胺等鹼之存在下，使用上述一般式（XXII)表示之化合物進行 51-烷基化，可藉以製造上述一般式（X X I I I )表示之化合物。所使用之溶劑可列舉如 yV,介-二曱基曱醯胺、丙酮 '氣化曱烷及該等之混合溶劑等。反應溫度通常為 0 °C〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但 312XP/發明說明書(補件)/94-07/94106583 46 ⑧ 1351400 通常為30分鐘〜1曰。步驟1 9 將上述一般式（X X I I I )表示之化合物，在惰性溶劑中，於多磷酸之存在下進行環化，可藉以製造上述一般式（X I V a ) 表示之苯并。塞吩衍生物。所使用之溶劑可列舉如苯、氯苯、甲苯等，反應溫度通常為室溫〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1小時〜1曰。(wherein L6 is a gas atom, a bromine atom or an iodine atom; R12 is a methyl group or an ethyl group, or both are bonded to form an extended ethyl group or a triadenylene group; and R1 to R4 and L1 are as defined above.) Step 1 8 The compound represented by the above general formula (XXI) is represented by the above general formula (XXII) in an inert solvent in the presence of a base such as potassium carbonate, carbonic acid, triethylamine or I-diisopropylethylamine. The compound is subjected to 51-alkylation to produce a compound represented by the above general formula (XXIII). The solvent to be used may, for example, be yV, di-mercaptodecylamine, acetone 'vaporized decane, and the like. The reaction temperature is usually from 0 ° C to the reflux temperature, and the reaction time varies depending on the starting materials or solvent used, the reaction temperature, etc., but the 312XP/invention specification (supplement)/94-07/94106583 46 8 1351400 is usually 30 minutes. ~1曰. Step 1 9 The compound represented by the above general formula (X X I I I ) can be cyclized in an inert solvent in the presence of polyphosphoric acid to produce the benzene represented by the above general formula (X I V a ). The phenanthrene derivative. The solvent to be used may, for example, be benzene, chlorobenzene or toluene. The reaction temperature is usually room temperature to reflux temperature, and the reaction time varies depending on the starting material or solvent used, the reaction temperature, etc., but usually 1 hour to 1 Torr. .

上述一般式（X I V )表示之化合物中，A3為硫原子、R4為氫原子之化合物，亦可依下述步驟2 0〜2 3製造。Among the compounds represented by the above general formula (X I V ), a compound wherein A3 is a sulfur atom and R4 is a hydrogen atom may be produced by the following steps 20 to 23.

R5 R3 步驟20 Ri, 甲醯基化LVR5 R3 Step 20 Ri, Hypermethylation LV

(XXIV) 步驟21 -► R3(XXIV) Step 21 -► R3

COOR,a (XXVII) 、CHO (XXV) HS 八 COOR13 (XXVI)COOR, a (XXVII), CHO (XXV) HS VIII COOR13 (XXVI)

(式中之R13為曱基或乙基；R1〜R3及L1如同上述定義。）步驟20 將上述一般式（X X I V )表示之化合物，1 )在惰性溶劑中，於 Ν, Ν, Ν' ，Ν’ -四曱基乙二胺、六甲基磷醞胺等添加劑之存在或不存在下，使用正丁基鋰 '第二丁基鋰、第三丁基鋰、二異丙基醯胺鋰等之鹼進行鋰化後；2)再使用/Κ, /V- 312ΧΡ/發明說明書(補件)/94-07/94 〗06583 47 1351400 二甲基甲醢胺進行甲醯基化；可藉以製造上述一般式（XXV) 表示之化合物。所使用之溶劑可列舉如四氫呋喃 '二乙鰱及該等之混合溶劑等，反應溫度於反應1 )中通常為-1 0 0 °c 〜0 °C ，於反應 2 )中通常為-1 0 0 °C〜室溫，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但於反應1 )通常為5分鐘〜5小時，於反應2)通常為5分鐘〜1日。步驟2 1(wherein R13 is fluorenyl or ethyl; R1 to R3 and L1 are as defined above.) Step 20 The compound represented by the above general formula (XXIV), 1) in an inert solvent, in hydrazine, hydrazine, hydrazine, In the presence or absence of an additive such as Ν'-tetradecylethylenediamine or hexamethylphosphonium, n-butyllithium 't-butyllithium, t-butyllithium, lithium diisopropylamide After the lithiation of the base; 2) re-use / Κ, /V- 312 ΧΡ / invention instructions (supplement) /94-07/94 〗 06583 47 1351400 dimethylformamide for mercapylation; The compound represented by the above general formula (XXV) is produced. The solvent to be used may, for example, be tetrahydrofuran 'diethyl hydrazine and a mixed solvent thereof, and the reaction temperature is usually -1 0 0 °c to 0 °C in the reaction 1), and usually -1 0 in the reaction 2). The reaction time varies depending on the starting material or solvent used, the reaction temperature, and the like, but the reaction 1) is usually 5 minutes to 5 hours, and the reaction 2) is usually 5 minutes to 1 day. Step 2 1

將上述一般式（X X V )表示之化合物，在惰性溶劑中，於三乙胺、怂二異丙基乙胺、碳酸鉀、碳酸鉋、第三丁醇鉀、氫化鈉等鹼之存在下，使用上述一般式（XXVI)表示之硫醇醋酸酯進行環化，可藉以製造上述一般式（X X V I I )表示之笨并噻吩衍生物。所使用之溶劑可列舉如％ 7K -二曱基甲醯胺、二曱基亞砜、四氫呋喃 '曱醇、乙醇、正丁醇及該等之混合溶劑等，反應溫度通常為室溫〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為5分鐘〜1曰。步驟22 將上述一般式（XXVII)表示之化合物，於氫氧化納、氫氧化鉀等鹼性物質之存在下進行水解，可藉以製造上述一般式（X X V I I I )表示之錄酸衍生物。所使用之溶劑可列舉如甲醇、乙醇、2 -丙醇、四氫呋喃、水及該等之混合溶劑等，反應溫度通常為室溫〜回流溫度，反應時間因所使用之原料物質或溶劑 '反應溫度等而異，但通常為I小時〜1曰。步驟23 312XP/發明說明書(補件)/94-07/94 ] 06583 48 ⑧ 1351400 將上述一般式（X X V I I I )表示之化合物，在惰性溶劑中’ 使用銅粉等觸媒進行脫碳酸，可藉以製造上述一般式（X丨v b) 表示之化合物。所使用之溶劑可列舉如喹啉等’反應温度通常為 1 0 0 °c〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為30分鐘〜1曰。本發明之上述一般式（I )表示之化合物中，以下述一般式（lb)表示之化合物，亦可依下述步驟24〜30製造。 R3The compound represented by the above general formula (XXV) is used in the presence of a base such as triethylamine, guanidinium diisopropylethylamine, potassium carbonate, carbonic acid planing, potassium butoxide or sodium hydride in an inert solvent. The thiol acetate represented by the above general formula (XXVI) is cyclized to produce the phenoxy thiophene derivative represented by the above general formula (XXVII). The solvent to be used may, for example, be % 7K - dimethyl carbamide, dimercapto sulfoxide, tetrahydrofuran 'decanol, ethanol, n-butanol, and the like, and the reaction temperature is usually room temperature to reflux temperature. The reaction time varies depending on the starting material or solvent used, the reaction temperature, etc., but is usually from 5 minutes to 1 Torr. Step 22 The compound represented by the above formula (XXVII) is hydrolyzed in the presence of a basic substance such as sodium hydroxide or potassium hydroxide to produce an acid-bearing derivative represented by the above general formula (X X V I I I ). The solvent to be used may, for example, be methanol, ethanol, 2-propanol, tetrahydrofuran, water or a mixed solvent thereof. The reaction temperature is usually room temperature to reflux temperature, and the reaction time depends on the starting material or solvent used. The difference is the same, but usually it is 1 hour ~ 1曰. Step 23 312XP/Invention Manual (Supplement)/94-07/94] 06583 48 8 1351400 The compound represented by the above general formula (XXVIII) can be produced by decarbonation using a catalyst such as copper powder in an inert solvent. The compound represented by the above general formula (X丨vb). The solvent to be used may, for example, be quinoline or the like. The reaction temperature is usually from 100 ° C to the reflux temperature, and the reaction time varies depending on the starting material or solvent used, the reaction temperature, etc., but is usually from 30 minutes to 1 Torr. In the compound represented by the above general formula (I) of the present invention, the compound represented by the following general formula (lb) may be produced by the following steps 24 to 30. R3

[式中之P為曱苯磺醯（tosyl)基、笨磺醯基等保護基； L7為氣原子、溴原子、碘原子、甲磺醯氧（m e s y 1 ο X y )基或曱苯石黃酿氧基；Q3為-C丨-6伸烧基_ 、 - C2-6伸稀基-、-匸2-6伸快基-、-〇丨-6伸炫<基-〇-、-〇丨-6伸坑基-S- 、 - C丨-6伸烷基- 0- C】-s伸烷基-、-C丨-6伸烷 49 312XP/發明說明書(補件)/94-07/94】06583 1351400 基- S- Ci-6 伸烧基-、- C0N(R8)- 、 - C 丨-6 伸烧基-C0N(R8) -或-C0N(R8) - Ch 伸烷基-;R1 〜R6、L1、 L2、G、G1及G2如同上述定義。][In the formula, P is a protecting group such as a tosyl group or a sulfonyl group; and L7 is a gas atom, a bromine atom, an iodine atom, a mesylate (mesy 1 ο X y ) group or a fluorene stone) Yellow-brown oxy; Q3 is -C丨-6 stretching base _, - C2-6 stretching base-, -匸2-6 stretching fast--, -〇丨-6 stretching 炫<基-〇-, -〇丨-6伸坑基-S-, -C丨-6alkylene- 0-C]-salkyl-,-C丨-6-desane 49 312XP/Invention Manual (supplement)/94 -07/94】06583 1351400 ke-S-C-6 Stretching base-,-C0N(R8)-, -C 丨-6 Stretching base-C0N(R8)- or -C0N(R8) - Ch Bases -; R1 to R6, L1, L2, G, G1 and G2 are as defined above. ]

步驟24 將上述一般式（X X X I X )表示之化合物，在惰性溶劑中，於氫化鈉、氫氧化鉀等鹼之存在下，使用曱苯磺醯氣 '笨磺醯氣等保護化試劑保護氮原子，可藉以製造上述一般式 (X X X )表示之化合物。反應所使用之溶劑可列舉如介，水-二曱基曱醯胺、二甲基亞砜、四氫呋喃、曱苯及該等之混合溶劑等，反應溫度通常為 0 °C〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1小時〜1曰。步驟25 將上述一般式（X X X )表示之化合物，1 )在惰性溶劑中，使用正丁基鋰、第二丁基鋰、第三丁基鋰等鋰化試劑進行鋰化；或 2 )在惰性溶劑中，於碘、1，2 -二溴乙烷等添加劑之存在下，使用鎂調製格任亞試劑；可藉以，製造上述一般式（X X X I )表示之化合物。使用於鋰化反應之溶劑，可列舉如四氫咬喃、二乙醚及該等之混合溶劑等，反應溫度通常為-1 0 0 °C〜0 °c，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1分鐘〜3小時。使用於調製格任亞試劑之溶劑，可列舉如四氫呋喃、二乙醚及該等之混合溶劑等，反應溫度通常為 o°c〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為 3 ] 2XP/發明說明書(補件)/94-07/94丨065S3 50 ⑧ 1351400 3 0分鐘〜5小時。步驟26Step 24: The compound represented by the above general formula (XXXIX) is protected with a protective agent such as sulfonium sulfonium sulfonate in an inert solvent in the presence of a base such as sodium hydride or potassium hydroxide to protect the nitrogen atom. The compound represented by the above general formula (XXX) can be produced. The solvent to be used in the reaction may, for example, be a water-dimercaptoamine, dimethyl sulfoxide, tetrahydrofuran, anthracene or the like, and the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is usually It varies depending on the starting material or solvent used, the reaction temperature, etc., but is usually from 1 hour to 1 Torr. Step 25: The compound represented by the above general formula (XXX), 1) is lithiated in an inert solvent using a lithiating reagent such as n-butyllithium, t-butyllithium or t-butyllithium; or 2) inert In the solvent, a magnesium-modulated genomic reagent is used in the presence of an additive such as iodine or 1,2-dibromoethane; whereby the compound represented by the above general formula (XXXI) can be produced. The solvent used for the lithiation reaction may, for example, be tetrahydroanion, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually -1 0 0 ° C to 0 ° C, and the reaction time is due to the raw material used or The solvent, the reaction temperature and the like may vary, but it is usually from 1 minute to 3 hours. The solvent used for the preparation of the genomic reagent may, for example, be tetrahydrofuran, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually from o ° c to reflux temperature, and the reaction time depends on the raw material or solvent used, the reaction temperature, and the like. Different, but usually 3] 2XP / invention manual (supplement) /94-07/94 丨065S3 50 8 1351400 3 0 minutes ~ 5 hours. Step 26

將上述一般式（XXXI)表示之化合物與上述一般式（Ga) 或（G b )表示之糖内酯，在惰性溶劑中進行縮合，可藉以製造上述一般式（X X X I I )表示之化合物。所使用之溶劑可列舉如四氫呋喃、二乙醚及該等之混合溶劑等，反應溫度通常為-1 0 0 °C〜室溫，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為5分鐘〜5小時。步驟27 將上述一般式（X X X I I )表示之化合物，在惰性溶劑中，於三氟化硼•二乙醚錯合物之存在下，使用三乙基矽烷、三異丙基矽烷等試劑進行還原，以脫去變旋異構位之羥基，可藉以製造上述一般式（XXXIII)表示之化合物。所使用之溶劑可列舉如乙腈、氣化甲烷、1，2 -二氣乙烷及該等之混合溶劑等，反應溫度通常為-20 °C〜室溫，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為3 0 分鐘〜1日。步驟28 將上述一般式（X X X I I I )表示之化合物，在惰性溶劑中，使用氫氧化鉀、氫氧化鈉等鹼進行水解，可藉以製造上述一般式（X X X I V )表示之脫保護體。所使用之溶劑可列舉如甲醇、乙醇、水、四氫呋喃、A介-二甲基曱醯胺及該等之混合溶劑等，反應溫度通常為 0 °C〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為 1 312XP/發明說明書(補件)/94-07/94〗065S3 51 ⑧ 1351400 小時〜2日。步驟29The compound represented by the above general formula (XXXI) and the sugar lactone represented by the above general formula (Ga) or (G b ) are condensed in an inert solvent to produce a compound represented by the above general formula (X X X I I ). The solvent to be used may, for example, be tetrahydrofuran, diethyl ether or a mixed solvent thereof, and the reaction temperature is usually -1 to 0 ° C to room temperature, and the reaction time varies depending on the starting material or solvent used, the reaction temperature, and the like. But usually it is 5 minutes to 5 hours. Step 27: The compound represented by the above general formula (XXXII) is reduced in an inert solvent in the presence of a boron trifluoride diethyl ether complex using a reagent such as triethyl decane or triisopropyl decane. The compound represented by the above general formula (XXXIII) can be produced by removing the hydroxyl group of the spinning moiety. The solvent to be used may, for example, be acetonitrile, vaporized methane, 1,2-diethane and a mixed solvent thereof, and the reaction temperature is usually -20 ° C to room temperature, and the reaction time is due to the raw material used or The solvent, reaction temperature, and the like vary, but it is usually from 30 minutes to 1 day. Step 28 The compound represented by the above general formula (X X X I I I ) is hydrolyzed in an inert solvent using a base such as potassium hydroxide or sodium hydroxide to produce a deprotected product represented by the above general formula (X X X I V ). The solvent to be used may, for example, be methanol, ethanol, water, tetrahydrofuran, A-dimethylamine, or a mixed solvent thereof, and the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is due to the raw materials used. The substance or solvent, reaction temperature, etc. vary, but usually 1 312XP / invention specification (supplement) /94-07/94〗 065S3 51 8 1351400 hours ~ 2 days. Step 29

將上述一般式（X X X I V )表示之化合物，在惰性溶劑中，於氫化鈉、氫化鉀、氫氧化鉀、正丁基鋰等鹼之存在下，使用上述一般式（XXXV)表示之化合物進行介-烷基化或介-醯基化，可藉以製造上述一般式（V b )表示之化合物。所使用之溶劑可列舉如 yV, /V -二曱基曱醮胺、四氫。夫味、二曱基亞颯 '甲笨及該等之混合溶劑等，反應溫度通常為〇°C 〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1小時〜1曰。步驟30 將上述一般式（V b )表示之化合物，1 )在惰性溶劑中，使用鈀碳粉末等鈀系觸媒進行接觸還原；或 2 )在惰性溶劑中，使用乙硫醇等試劑，於三氟化硼•二乙醚錯合物等酸之存在下脫去苄基，可藉以製造本發明之上述一般式Ub) 表示之化合物。接觸還原所使用之溶劑可列舉如曱醇、乙醇、醋酸乙酯、四氫呋喃、醋酸及該等之混合溶劑等，反應溫度通常為 0 °C〜回流溫度，反應時間因所使用之原料物質或溶劑 '反應溫度等而異，但通常為I小時〜2曰。酸處理所使用之溶劑可列舉如氣化曱烷、1，2 -二氣乙烷、乙腈及該等之混合溶劑等，反應溫度通常為 0 °C〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為3 0分鐘〜1日。上述一般式（II)表示之化合物中，以下述一般式（lid) 312XP/發明說明書(補件)/9107/94】〇6583 52 ⑧ 1351400The compound represented by the above general formula (XXXIV) is subjected to the use of a compound represented by the above general formula (XXXV) in the presence of a base such as sodium hydride, potassium hydride, potassium hydroxide or n-butyllithium in an inert solvent. The alkylation or the thiolation can be used to produce the compound represented by the above general formula (V b ). The solvent to be used may, for example, be yV, /V-dimercaptoamine or tetrahydrogen. Fused, diterpenoid, and a mixture of these solvents, the reaction temperature is usually 〇 ° C ~ reflux temperature, the reaction time varies depending on the raw material or solvent used, the reaction temperature, etc., but usually 1 hour ~ 1 曰. Step 30: The compound represented by the above general formula (V b ), 1) is contact-reduced with an palladium-based catalyst such as palladium carbon powder in an inert solvent; or 2) an agent such as ethanethiol is used in an inert solvent. The compound represented by the above general formula Ub) of the present invention can be produced by removing a benzyl group in the presence of an acid such as boron trifluoride diethyl ether complex. The solvent used for the contact reduction may, for example, be decyl alcohol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid or a mixed solvent thereof, and the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is due to the raw material or solvent used. 'The reaction temperature varies, but it is usually 1 hour to 2 曰. The solvent used for the acid treatment may, for example, be gasified decane, 1,2-dioxaethane, acetonitrile or a mixed solvent thereof, and the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is due to the raw materials used. The substance or solvent, the reaction temperature, and the like may vary, but it is usually from 30 minutes to 1 day. Among the compounds represented by the above general formula (II), the following general formula (lid) 312XP / invention specification (supplement) / 9107/94 〇 6583 52 8 1351400

(式中之 Q4為氧原子或硫原子；Q5為-C丨-6伸烷基-;A3 為氧原子、硫原子或NR9 ; L8為氣原子、溴原子、碘原子、甲磺醯氧基或曱苯磺醯氧基；R1〜R6及L1如同上述定義。）步驟3 1 將上述一般式（X X X V I )表示之化合物，在惰性溶劑中，於氫化鈉、氫氧化鉀、第三丁醇鉀、碳酸鉋等鹼之存在下’ 與上述一般式（XXXVII)表示之化合物進行縮合，可藉以製造上述一般式（I I d )表示之化合物。縮合反應所使用之溶劑可列舉如四氫呋喃、介，# -二甲基曱醯胺、二曱基亞硬、丙酮、甲醇及該等之混合溶劑等，反應溫度通常為 0°C〜回流溫度，反應時間因所使用之原料物質或溶劑、反應溫度等而異，但通常為1小時〜1曰。上述一般式（II)表示之化合物中，以下述一般式（lie) 表示之化合物，亦可依下述步驟32製造。(wherein Q4 is an oxygen atom or a sulfur atom; Q5 is -C丨-6 alkyl group; A3 is an oxygen atom, a sulfur atom or NR9; L8 is a gas atom, a bromine atom, an iodine atom, a methanesulfonyloxy group; Or phenylsulfonyloxy; R1 to R6 and L1 are as defined above.) Step 3 1 The compound represented by the above general formula (XXXVI), in an inert solvent, sodium hydride, potassium hydroxide, potassium butoxide The compound represented by the above general formula (II d ) can be produced by condensation with a compound represented by the above general formula (XXXVII) in the presence of a base such as a carbonic acid planer. The solvent to be used in the condensation reaction may, for example, be tetrahydrofuran, meta-, #-dimethyldecylamine, dimercapto, hard, acetone, methanol or a mixed solvent thereof, and the reaction temperature is usually from 0 ° C to reflux temperature. The reaction time varies depending on the raw material or solvent to be used, the reaction temperature, etc., but is usually from 1 hour to 1 Torr. Among the compounds represented by the above formula (II), the compound represented by the following general formula (lie) may be produced in the following step 32.

312XP/發明說明書(補件)/94-〇7/94106583 ⑧ 1351400312XP/Invention Manual (supplement)/94-〇7/94106583 8 1351400

(式中之 Q6為氧原子或硫原子；Q7為單鍵或-C < - 6伸基-;L9為氣原子、溴原子、碘原子、曱磺醯氧基或曱磺醯氧基；R1〜R6、L1及A3如同上述定義。）步驟32 將上述一般式（X X X I X )表示之化合物，在惰性溶劑中於氫化鈉、氮氡化鉀、第三丁醇鉀、碳酸铯等鹼之存在下與上述一般式（XXXVIII)表示之化合物進行縮合，可藉以造上述一般式（I I e )表示之化合物。縮合反應所使用之溶可列舉如四氫呋喃、見水-二甲基甲醯胺、二甲基亞砜、酮、甲醇及該等之混合溶劑等，反應溫度通常為 0°C〜流溫度，反應時間因所使用之原料物質或溶劑、反應溫等而異，但通常為1小時〜1曰。於上述製造方法中，在具有羥基、胺基及/或羧基之合物中可依需要適當以常法任意導入保護基後提供反應又，保護基在後續之步驟可適當以常法脫去。於前述製造方法所得之本發明之上述一般式（I)表示化合物，可使用屬習知分離方法之分級再結晶法、使用析法之精製法、溶劑萃取法、固相萃取法等進行分離純精製。本發明之上述一般式（I )表示之縮合雜環衍生物，可常法製成其藥理學上容許之鹽。此種鹽可列舉如與鹽酸溴化氫酸、碘化氫酸、硫酸、硝酸、磷酸等無機酸之酸成鹽；與犧酸 '醋酸、甲石黃酸、苯績酸、對甲苯項酸、酸、檸檬酸、琥珀酸、酒石酸、反丁烯二酸、丁酸、草酸烷苯製劑丙回度化〇之色化依、加丙 3I2XP/發明說明書(補件)/94-07/94106583 54 1351400 丙二酸、順丁烯二酸 '乳酸、蘋果酸、碳酸、麩胺酸 '天冬胺酸等有機酸之酸加成鹽；與鈉鹽'鉀鹽等無機鹼之鹽；與/V-曱基-D -還原葡萄糖胺（glucamine)'/V, r -二苄基乙二胺、2 -胺基乙醇、三（羥甲基）胺基曱烷、精胺酸、離胺酸等有機鹼之加成鹽。本發明之上述一般式（I )表示之化合物，亦包含與水或乙醇等醫藥品所容許溶劑之溶劑合物。(wherein Q6 is an oxygen atom or a sulfur atom; Q7 is a single bond or -C<-6 extension group;; L9 is a gas atom, a bromine atom, an iodine atom, a sulfonyloxy group or a sulfonyloxy group; R1 to R6, L1 and A3 are as defined above.) Step 32 The compound represented by the above general formula (XXXIX) is present in an inert solvent in the presence of a base such as sodium hydride, potassium hydride, potassium butoxide or cesium carbonate. The compound represented by the above general formula (IIe) can be formed by condensation with a compound represented by the above general formula (XXXVIII). Examples of the solvent used in the condensation reaction include tetrahydrofuran, water-dimethylformamide, dimethyl sulfoxide, ketone, methanol, and the like, and the reaction temperature is usually 0 ° C to a flow temperature, and the reaction is carried out. The time varies depending on the raw material or solvent used, the reaction temperature, etc., but it is usually from 1 hour to 1 Torr. In the above-mentioned production method, in the case of having a hydroxyl group, an amine group and/or a carboxyl group, a protective group may be optionally introduced by a usual method, and a reaction may be carried out, and the protective group may be appropriately removed by a usual method in a subsequent step. The above general formula (I) of the present invention obtained by the above production method represents a compound which can be isolated and purified by a fractional recrystallization method which is a conventional separation method, a purification method using an analytical method, a solvent extraction method, a solid phase extraction method, or the like. refined. The condensed heterocyclic derivative represented by the above general formula (I) of the present invention can be prepared into a pharmacologically acceptable salt by a usual method. Such a salt may be, for example, a salt with an acid of a mineral acid such as hydrogen bromide hydrochloride, hydrogen iodide acid, sulfuric acid, nitric acid or phosphoric acid; and an acid of acetic acid, methycein, phenyl acid, and p-toluene. , acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid and alkane benzene preparations, C, y, y, y,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 54 1351400 malonic acid, maleic acid 'lactic acid, malic acid, carbonic acid, glutamic acid 'aspartic acid and other organic acid acid addition salt; and sodium salt 'potassium salt and other inorganic base salt; and / V-mercapto-D-reducing glucamine'/V, r-dibenzylethylenediamine, 2-aminoethanol, tris(hydroxymethyl)aminodecane, arginine, lysine The addition salt of an organic base. The compound represented by the above general formula (I) of the present invention also contains a solvate of a solvent which is compatible with a pharmaceutical product such as water or ethanol.

本發明之上述一般式（I )表示之縮合雜環衍生物及其前驅藥中，具有不飽和鍵之化合物有順式（/)化合物及反式（幻化合物2種幾何異構體存在，於本發明中可使用其任一種化合物。本發明之上述一般式（I )表示之縮合雜環衍生物及其前驅藥中，除糖部分外具有不對稱碳原子之化合物，有β構型化合物與51構型化合物之2種光學異構體存在，於本發明中可使用任一光學異構體或此等光學異構體之混合物。本發明之上述一般式（I )表示之化合物之前驅藥，可使用相當之鹵化物等前驅藥化試劑，依常法將適當構成前驅藥之基導入選擇自上述一般式（I)表示之化合物之羥基、胺基及環狀胺基（吡唑環、哌畊環）等中之 1個以上任意之基，再依需要以適當常法分離精製而製成。使用於羥基或胺基之構成前驅藥之基，可列舉如C2-?S|基、C,-6烷氧（C2-7 酿）基、C2-7院氧趙（C2-7醯）基、C2-7烧氧隸基、Ce-ic芳（Ci-i 烷氧羰）基、C , - 6烷氧（C 2 - 7烷氧羰）基等；使用於環狀胺基之構成前驅藥之基，可列舉如C 2 - 7醯基、C I - 6烧氧（C 2 - 7醯） 3 ] 2XP/發明說明書(補件)/94-07/94 ] 〇65谷3 55 ⑧ 1351400 基、Cz-7统氧M(Cz-7酿）基、Cz-7炫氧续基' C6-I。芳（Cz-7炫氧羰）基、Ci-6烷氧（C2-7烷氧羰）基、（C2-7醯氧基）甲基、 l-(C2-7醯氧基）乙基、（C2-7烷氧羰）氧曱基、1- 〔（C2-7 烷氧羰）氧〕乙基、（C3-7環烷）氧羰基氧曱基、1- 〔（C3-7In the condensed heterocyclic derivative represented by the above general formula (I) of the present invention and a precursor thereof, a compound having an unsaturated bond has a cis (/) compound and a trans (phantom compound 2 geometric isomers present in Any of the compounds of the present invention can be used in the condensed heterocyclic derivative represented by the above general formula (I) and a precursor thereof, and a compound having an asymmetric carbon atom other than the sugar moiety, and a β configuration compound and The two optical isomers of the 51-configuration compound are present, and any optical isomer or a mixture of such optical isomers may be used in the present invention. The compound of the above general formula (I) of the present invention is pre-drug-exposed. A precursor compound which is a suitable precursor can be introduced into a hydroxyl group, an amine group and a cyclic amine group (pyrazole ring, which are selected from the compound represented by the above general formula (I) by a conventional method using a prodrug reagent such as a halide. One or more arbitrary groups such as a piperidine ring and the like are prepared by separation and purification by an appropriate conventional method as needed. Examples of the base of the constituent precursor of the hydroxyl group or the amine group include a C2-?S| group. C,-6 alkoxy (C2-7) , C2-7, Oxygen Zhao (C2-7醯), C2-7, Oxygen, Ce-ic, Ci-i, C, -6 alkoxy a carbonyl group or the like; a group used as a precursor of a cyclic amine group, such as a C 2 - 7 fluorenyl group, a CI 6 -oxygen (C 2 - 7 醯) 3 ] 2 XP / invention specification (supplement) /94-07/94 ] 〇65谷3 55 8 1351400 base, Cz-7 oxygen M (Cz-7) base, Cz-7 oxo thiol 'C6-I. aryl (Cz-7 oxocarbonyl Base, Ci-6 alkoxy (C2-7 alkoxycarbonyl), (C2-7 decyloxy)methyl, 1-(C2-7 decyloxy)ethyl, (C2-7 alkoxycarbonyl) Oxime, 1-[(C2-7 alkoxycarbonyl)oxy]ethyl, (C3-7 cycloalkane)oxycarbonyloxycarbonyl, 1-[(C3-7

環烷）氧羰基氧〕乙基等。0-6烷氧（Ci-7醯）基為被上述Ci-e 烷氧基取代之上述C2-7醯基，C2-7烷氧羰（C2-7醯）基為被上述Cz-7烷氧羰基取代之上述Cm醯基，C«-6烷氧（C2-7烷氧羰）基為被上述C，-6烷氧基取代之上述Cz-7烷氧羰基，（C2-7 醯氧基）甲基為被上述C2-7醯基取代之羥曱基，1- (C2-7 醯氧基）乙基為被上述C2-7醯基0 -取代之1-羥乙基，（C2-7 烷氧羰）氧化曱基為被上述 C2-7烷氧羰基取代之羥曱基，1-〔（C2-7烷氧羰）氧〕乙基為被上述C2-7烷氧羰基0-取代之 1-羥乙基。又（C3-7環烷）氧羰基為具有上述 C3-7 環烷基之環狀烷氧羰基，（C 3 - 7環烷）氧羰氧化曱基為被上述（C 3 - 7環烷）氧羰基 0 -取代之羥曱基，1 - 〔（ C 3 - 7環烷）氧羰羥〕乙基為被上述（C 3 - 7環烷）氧羰基0 -取代之1 -羥乙基。此外，構成前驅藥之基可列舉如葡哌喃聚糖基或吡喃半乳糖基，以導入葡哌喃聚糖氧基或吼喃半乳糖氧基之 4位或6位之經基較好，而以導入葡略喃聚糖氧基之4位或6位之經基更好。本發明之上述一般式（I )表示之縮合雜環衍生物，例如於下述人體S G L T 1或S G L T 2活性抑制作用確認試驗中，係表現強大之人體S G L T 1或S G L T 2活性抑制作用。因此，本發明之上述一般式（I )表示之縮合雜環衍生物，在小腸中表 312XP/發明說明書(補件)/94-07/94106583 56 ⑧ 現優異之人體SGLT1活性抑制作用，或於腎臟中表現優異 :SGLT2活性抑制作用，可顯著抑制血糖值之上升，或顯 :減低血糖值。是故本發明之上述—般式⑴表示之縮合雜物其藥理學上容許之鹽及其前驅帛，作為飯後高血糖抑制劑、葡萄…異常患者轉……阻止劑，及與小腸中之SGLT1活化及腎臟中之·τ2活性相關之如糖尿病、“糖耐性異常、糖尿病性併發症（如視網膜症、神經障礙、早礙腎疾病、>貝’麝、大血管症）、肥胖症、高肤島素血症、高脂血症 '高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常、動脈粥樣硬化症、高血壓、誉血性心竭、浮腫、高尿酸企症、痛風等因高血糖症引起之疾病之預防或治療藥極為有用。發月之化合物可與至少1種下述藥劑適當組合使用。可與本發明之化合物組合使用之藥劑，可列舉如膜島素敏感性增強齊丨、糖吸收抑制劑、雙胍藥、姨島素分泌促進劑、SGLT2活性抑制劑、肤島素或騰島素類似物、升糖 :文體拮抗劑 '騰島紊受體激酶刺激劑、三肽冑π抑制肽酶IV抑制劑、蛋白質酪胺醆磷酸酶U抑制劑、 :酿峨酸化酶抑制劑、葡萄糖-6'碟酸酶抑制劑、果糖二碟酸酶抑制劑、丙，酸去氫酶抑制劑、肝骑新生抑制劑、D _ 手肌醇（D-chiFC)inQsltQl)、肝酿合成酵素激酶—3抑制劑升素樣胜肽1 '升糖素樣胜肽_ 1類似物、升糖素樣胜肽_ 1促效劑香料素 '香樹素類似物、香樹素促效劑、醛糖還原酶抑制劑、值期糖化最終產物（advanced glycation endproducts)生 57 312XP/發明說明書(補件)/94·〇7/94106583 1351400 成抑制劑、蛋白質激酶C抑制劑、τ -胺基丁酸受體拮抗劑、納離子通道拮抗劑、轉錄因子NF - /c Β抑制劑、脂質過氧化酶抑制劍、水-乙醯化-α -連結酸性二肽酶（於a c e t y 1 a t e d - α -linked-acid-dipeptidase)抑制劑、胰島素樣生長因子_ I、血小板來源生長因子（PDGF )、血小板來源生長因子（PDGF )類似物 (如 PDGF - AA、PDGF - 、PDGF - AB)、上皮增殖因子（EGF)、神Cycloalkane)oxycarbonyloxy]ethyl and the like. The 0-6 alkoxy (Ci-7 fluorene) group is the above C2-7 fluorenyl group substituted by the above Ci-e alkoxy group, and the C2-7 alkoxycarbonyl (C2-7 fluorene) group is the above Cz-7 alkane. The above Cm thiol group substituted by an oxycarbonyl group, the C«-6 alkoxy (C2-7 alkoxycarbonyl) group is the above Cz-7 alkoxycarbonyl group substituted by the above C, -6 alkoxy group, (C2-7 oxime) The methyl group is a hydroxymethyl group substituted by the above C2-7 fluorenyl group, and the 1-(C2-7 decyloxy)ethyl group is a 1-hydroxyethyl group substituted by the above C2-7 fluorenyl group, (C2 -7 alkoxycarbonyl) fluorenyl group is a hydroxymethyl group substituted by the above C2-7 alkoxycarbonyl group, and 1-[(C2-7 alkoxycarbonyl)oxy]ethyl group is the above C2-7 alkoxycarbonyl group 0- Substituted 1-hydroxyethyl. Further, the (C3-7 cycloalkane)oxycarbonyl group is a cyclic alkoxycarbonyl group having the above C3-7 cycloalkyl group, and the (C 3-7 cycloalkane)oxycarbonyloxycarbonyl group is the above (C 3 - 7 naphthenic). Oxycarbonyl 0-substituted hydroxyindenyl, 1-[(C 3 -7 cycloalkane)oxycarbonyl]ethyl is 1-hydroxyethyl substituted by the above (C 3 -7 cycloalkane)oxycarbonyl. Further, the group constituting the prodrug may, for example, be a glucomannan group or a galactopyranosyl group, and it is preferably introduced into the 4- or 6-position of the glucomannanoxy group or the galactopyranosyloxy group. Further, it is more preferable to introduce a radical of the 4- or 6-position of the glucomannanoxy group. The condensed heterocyclic derivative represented by the above general formula (I) of the present invention is, for example, a human S G L T 1 or S G L T 2 activity inhibitory activity which is strong in the following human S G L T 1 or S G L T 2 activity inhibitory confirmation test. Therefore, the condensed heterocyclic derivative represented by the above general formula (I) of the present invention is excellent in the inhibition of human SGLT1 activity in the small intestine, Table 312XP/invention specification (supplement)/94-07/94106583 56 8 Excellent performance in the kidney: SGLT2 activity inhibition, can significantly inhibit the rise in blood sugar levels, or significantly: reduce blood sugar levels. Therefore, the pharmaceutically acceptable salt and its precursor of the condensed product represented by the above general formula (1) of the present invention are used as postprandial hyperglycemia inhibitors, grapes, abnormal patients, inhibitors, and in the small intestine. Activation of SGLT1 and diabetes-related activities in the kidney such as diabetes, "sugar tolerance, diabetic complications (such as retinopathy, neurological disorders, early-onset kidney disease, > bei's disease, macrovascular disease), obesity, Hyperkalemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis, hypertension, blood stasis, edema, hyperuricemia, gout It is extremely useful to prevent or treat a disease caused by hyperglycemia, etc. The compound of the genus can be used in combination with at least one of the following agents. The agent which can be used in combination with the compound of the present invention may be exemplified by membrane sensitization. Sexually enhanced Qiqi, sugar absorption inhibitor, biguanide, yoghurt secretion promoter, SGLT2 activity inhibitor, cutaneous or tamsin analogue, sucrose: stylistic antagonist 'Tengdao neutrophil receptor kinase thorn Activator, tripeptide 胄π inhibitor peptidase IV inhibitor, protein tyramine phosphatase U inhibitor, glucosinolate inhibitor, glucose-6' dishhenase inhibitor, fructose dibasase inhibitor, C, acid dehydrogenase inhibitor, liver riding newborn inhibitor, D _ hand inositol (D-chiFC) inQsltQl), liver brewing enzyme kinase 3 inhibitor leptin-like peptide 1 'glycoside-like peptide _ 1 analogue, glycoside-like peptide _ 1 agonist, perfumer's fragrant tree analog, auxin agonist, aldose reductase inhibitor, advanced glycation endproducts 57 312XP/Inventive Manual (Supplement)/94·〇7/94106583 1351400 Inhibitor, protein kinase C inhibitor, τ-aminobutyric acid receptor antagonist, nanochannel antagonist, transcription factor NF - /c Indole inhibitor, lipid peroxidase inhibits sword, water-acetylated-α-linked acid dipeptidase (in acety 1 ated - α -linked-acid-dipeptidase) inhibitor, insulin-like growth factor _ I, platelet source Growth factor (PDGF), platelet-derived growth factor (PDGF) analogs (eg PDGF-AA) PDGF -, PDGF - AB), epithelial growth factor (EGF), God

經生長因子、肉鹼衍生物、尿核苷、5 -羥基-1 -曱基乙内醯脲、 EGB - 761 ' 必莫克默（bimoclomol)、舒得塞（sulodexide)、 Y - 1 2 8、止瀉劑、瀉劑、羥甲基戊二醯輔酶A還原酶抑制劑、纖維酸衍生物、/5 3 -腎上腺素受體促效劑、醯基輔酶A :膽固醇醯基轉移酶抑制劑、丙丁酚、曱狀腺受體促效劑、膽固醇吸收抑制劑、脂酶抑制劑、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、肉鹼棕櫚醯基轉移酶抑制劑、鯊烯合成酶抑制劑、低比重脂蛋白受體增強劑、菸鹼酸衍生物、膽汁酸吸附劑、鈉共軛膽汁酸轉移因子抑制劑、膽固醇酯轉移蛋白抑制劑、食慾抑制劑、血管升壓素轉移酶抑制劑、中性肽鏈内切酶抑制劑、血管升壓素I I受體拮抗劑、内皮素轉移酶抑制劑、内皮素受體拮抗劑、利尿劑、鈣離子拮抗劑、血管擴張性降血壓劑、交感神經阻斷劑、中柩性降血壓劑、α 2 -腎上腺素受體促效劑、抗血小板劑、尿酸生成抑制劑、尿酸排泄促進劑及尿鹼性化劑等。在將本發明之化合物與上述藥劑之1種或以上組合使用之情況，本發明包含作為單一製劑同時投藥、作為各別製劑由相同或不同之投藥途徑同時投藥及作為各別製劑由相 312ΧΡ/發明說明書(補件)/94-07/SM106583 58 ⑧ 1351400 同或不同之投藥途徑間隔投藥等任一投藥形態，而本發明之化合物與上述藥劑組合而成之醫藥亦包含如上述作為單一製劑之投藥形態及作為組合各別製劑之投藥形態。本發明之化合物經由與1種或以上之上述藥劑適當組合使用，可獲得對上述疾病之預防或治療方面相加效果以上之有利效果。或，相較於單獨使用之情況，可減少其使用量’並可避免或減輕併用藥劑之副作用。Growth factor, carnitine derivative, uridine, 5-hydroxy-1-mercaptoinouramide, EGB-761 'bimoclomol, sulodexide, Y-1 2 8 , antidiarrheal, laxative, hydroxymethyl pentane coenzyme A reductase inhibitor, fibric acid derivative, /5 3 -adrenergic receptor agonist, 醯Kymase A: cholesterol thiol transferase inhibitor , probucol, sputum receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyl transferase inhibitor , squalene synthetase inhibitor, low specific gravity lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium conjugated bile acid transfer factor inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, blood vessel a vasopressin transferase inhibitor, a neutral endopeptidase inhibitor, a vasopressin II receptor antagonist, an endothelin transferase inhibitor, an endothelin receptor antagonist, a diuretic, a calcium ion antagonist, Vasodilating hypotensive agent, sympathetic blocker, Bier of hypotensive agents, α 2 - adrenergic receptor agonists, antiplatelet agents, uric acid generation inhibitors, uricosuric agent and urinary alkalization agent. In the case where the compound of the present invention is used in combination with one or more of the above-mentioned agents, the present invention comprises simultaneous administration as a single preparation, simultaneous administration as a separate preparation by the same or different administration routes, and as a separate preparation from the phase 312ΧΡ/ BRIEF DESCRIPTION OF THE INVENTION (Supplement) /94-07/SM106583 58 8 1351400 Any administration form such as the same or different administration route, and the combination of the compound of the present invention and the above-mentioned agent also includes the above as a single preparation. The form of administration and the form of administration as a combination of the respective preparations. When the compound of the present invention is used in an appropriate combination with one or more of the above-mentioned agents, an advantageous effect of the above-described effects of the above-mentioned diseases on the prevention or treatment can be obtained. Alternatively, the amount of use can be reduced as compared to the case of use alone, and the side effects of the combined use agent can be avoided or alleviated.

以下例示組合使用的藥劑之具體化合物及適合處理之疾病，但本發明之内容並不限定於此等，具體化合物係包括其遊離體及/或其藥理學上容許之鹽。騰島素敏感性增強劑可列舉如曲格列酮 (trogiitazone)、鹽酸比奥格列明（pyoglitazone HC1)、順丁稀二酸洛西格列酮（rosiglitazone maleate)、達格列酮鈉（darglitazone Na) 、 GI- 262570 、伊沙格列酮 (i sag 1i tazone )、LG - 1 0 0 6 4 1、NC - 2100、T - 174、 DRF - 2189、CLX - 0 9 2 1 ' CS - 011、GW - 1929、西格列酮 (ciglitazone)、安格列嗣納（englitazone Na)、NIP - 221 等過氧化酶體增殖藥活性受體 y 促效劑，G W - 9 5 7 8、 BM - 1 7 0 744 等過氧化體增殖藥活性受體 a 促效劑， GW - 409544、KRP - 297、NN - 622' CLX - 0940、LR - 90、 SB - 219994、DRF - 4158、DRF - MDX8等過氧化體增殖藥活性受體 a / ί 促效劑，ALRT- 268'AGN- 4204、MX- 6054、 AGN - 194204、LG - 100754、倍沙樂添（bexarotene)等類視色素（retionoid)X受體促效劑，及樂力散（reglixane)、 312XP/發明說明書(補件)/94-〇7m 106583 59 ⑧ 1351400Specific compounds of the agent to be used in combination and diseases suitable for the treatment are exemplified below, but the content of the present invention is not limited thereto, and the specific compound includes a free form thereof and/or a pharmacologically acceptable salt thereof. Examples of the sensitization enhancer of the tamsin may include trogiitazone, pyoglitazone HCl, rosiglitazone maleate, and dapagliflozin sodium. Darglitazone Na) , GI- 262570 , i sag 1i tazone , LG - 1 0 0 6 4 1 , NC - 2100, T - 174, DRF - 2189, CLX - 0 9 2 1 ' CS - 011, GW-1929, ciglitazone, englitazone Na, NIP-221, etc. Peroxisome proliferator active receptor y agonist, GW - 9 5 7 8 , BM - 1 7 0 744 and other peroxisome proliferator active receptor a agonists, GW - 409544, KRP - 297, NN - 622' CLX - 0940, LR - 90, SB - 219994, DRF - 4158, DRF - MDX8 Such as peroxisome proliferator active receptor a / ί agonist, ALRT- 268'AGN-4204, MX- 6054, AGN-194204, LG-100754, bexarotene and other retinoids X receptor agonist, and reglixane, 312XP/invention manual (supplement)/94-〇7m 106583 59 8 1351400

ΟΝΟ - 5816' MBX - 102' CRE - 1 6 2 5 ' FK - 6]4、CLX - 0901、 CRE- 1633'NN- 2344'BM- 13125'BM- 501050'HQL- 975' CLX - 0900、MBX - 668、MBX - 675、S- 15261、GW - 544、 AZ - 24 2 ' LY - 510929、AR - H049020、GW - 501516 等其他胰島素敏感性增強劑。胰島素敏感性增強劑特別有利於治療糖尿病、葡萄糖耐性異常、糖尿病性併發症、肥胖症、高胰島素血症、高脂血症、高膽固醇血症、高三酸甘油脂酯血症、脂肪代謝異常、動脈粥樣硬化症等，同時由於改善在末梢之胰島素剌激傳達機制之異常，而促進血液中葡萄糖攝取進入組織中以降低血糖值，故對糖尿病、葡萄糖耐性異常、高胰島素血症之治療更好。糖吸收抑制劑可列舉如糖祿（a c a r b 〇 s e )、包格里糖 (voglibose)、米格里多（miglitol) 、 CKD- 711 、易美格列替（emiglitate) 、 MDL-25，637 、甘味格里糖 (camiglibose)、MDL-73,945等α-葡萄糖苷酶抑制劑， AZM - 12 7 等 α - 澱粉酶抑制劑、國際公開公報 W002/098893號、國際公開公報W02004/014932號等記載之S G L Τ 1活性抑制劑等化合物。糖吸收抑制劑特別有利於治療糖尿病、葡萄糖耐性異常、糖尿病性併發症、肥胖症、高胰島素血症，同時由於能夠抑制食物中所含碳水化合物在消化道中進行酵素消化，而抑制或延緩體内吸收葡萄糖，故對葡萄糖耐性異常之治療更好。雙胍藥可列舉如苯乙雙胍（phenformin)、鹽酸丁福明 (buformin HC1)、鹽酸曱福明（metoformin HC1)等。雙胍 312XP/發明說明書(補件)/94-〇7/94丨06583 60 ⑧ 1351400 藥特別有利於治療糖尿病、葡萄糖对性異常、糖尿病性併發症 '高姨島素血症’同時由於在肝臟抑制糖質新生之作用、在組織促進厭氣性解糖作用及在末梢之胰島素抗抬性改善作用等而降低血糖值’故對糖展病、葡萄糖耐性異常、高联島素血症之治療更好。肤島素分泌促進劑可列舉如甲笨丁脸[ + + .,. ^ 牧（tolbutamide)、ΟΝΟ - 5816' MBX - 102' CRE - 1 6 2 5 ' FK - 6]4, CLX - 0901, CRE- 1633'NN- 2344'BM- 13125'BM- 501050'HQL- 975' CLX - 0900, MBX - 668, MBX-675, S-1515, GW-544, AZ-24 2 'LY-510929, AR-H049020, GW-501516 and other insulin sensitivity enhancers. Insulin sensitivity enhancers are particularly beneficial for the treatment of diabetes, glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, Atherosclerosis, etc., at the same time, because of the abnormality of the mechanism of insulin stimulation in the peripheral end, and promote the glucose uptake into the tissue to lower the blood sugar level, it is more effective in treating diabetes, glucose tolerance, and hyperinsulinemia. it is good. The sugar absorption inhibitors may, for example, be acarb 〇se, voglibose, miglitol, CKD-711, emiglitate, MDL-25, 637, Α-glucosidase inhibitors such as camiglibose, MDL-73, 945, α-amylase inhibitors such as AZM - 12 7 , International Publication No. WO 02/098893, and International Publication No. WO2004/014932 SGL Τ 1 compound such as activity inhibitor. Sugar absorption inhibitors are particularly beneficial for the treatment of diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, and inhibit or delay the body by inhibiting the digestion of carbohydrates in food in the digestive tract. Glucose absorption, so the treatment of abnormal glucose tolerance is better. Examples of the bifed drug include phenformin, buformin HC1, metoformin HC1, and the like. Double 胍 312XP / invention manual (supplement) / 94-〇7/94 丨 06583 60 8 1351400 The drug is particularly beneficial for the treatment of diabetes, glucose abnormalities, diabetic complications 'sorghum sputum' and also due to inhibition in the liver The role of gluconeogenesis, the promotion of anaerobic saccharification in tissues and the improvement of insulin resistance in the periphery, etc., lower blood sugar levels, so the treatment of gluconeogenesis, impaired glucose tolerance, and hyper-isidemia is more it is good. The skin stimulating agent can be exemplified by a pedicure [+ + ., . ^ tolbutamide,

氯碌丙腺（chlorpropamide)、妥拉明（t〇lazamide)、醋續環己腺（acetohexamide)、格列克比邁（glycl〇pyramide)、格列本腺或乙續己腺（glyburide 0r glibenclamide)、格列齊特 UlicUzide) 、 1- 丁基_ 3 -間胺醖尿素 (1 - butyl - 3 - metanilylurea)、卡丁邁（carbutamide)、甲確冰膝（glibornuride)、格列。比畊（glipzide)、格列喹酮（g 1 i q u i d ο η )、格列索沙比得（g丨丨s 〇 χ e p丨d )、格列丁噻唑 (glybuthiazol)、格列布唑（giybuz〇u)、格列六邁 (glyhexamide)、格列密定鈉（glymidine Na)、格列平脲 (glypinamide)、笨璜丁脲（phenbutamide)、曱磺環己脲 (tolcyclamide)、格列美服（giimepjride)、納得格列而十 (n a t e g 1 i n i d e )、米地格列耐約水合物（m i t i g 1丨n i d e Ca-hydrate)、瑞巴格列耐（repaglinide)等，並包含 R 0 - 2 8 - 1 6 7 5等葡萄糖激酶活性化劑。肤島素分泌促進劑特別有利於治療糖尿病、葡萄糖耐性異常、糖尿病性併發症’同時由於作用於騰臟冷細胞以增加胰島素分泌而降低血糖值，故對糖尿病、葡萄糖耐性異常之治療更好。 S G L Τ 2活性抑制劑可列舉如τ _丨〇 9 5及日本專利特開平 ⑧ 312ΧΡ/發明說明書(補件)/94-〇7/94106583 1351400Chlorpropamide, t〇lazamide, acetohexamide, glycl〇pyramide, glibenclamide or glyburide 0r glibenclamide ), gliclazide (UlicUzide), 1-butyl- 3 - metanilylurea, carbutamide, glibornuride, glibenclamide. Glitz (glipzide), gliclazide (g 1 iquid ο η ), glizazapine (g丨丨s 〇χ ep丨d ), glybutthiazole (glybuthiazol), glibazole (giybuz 〇u), glyhexamide, glymidine Na, glypinamide, phenbutamide, tolcyclamide, glime (giimepjride), nateg 1 inide, mitig 1丨nide Ca-hydrate, repaglinide, etc., and contains R 0 - 2 8 - 1 6 7 5 and other glucokinase activators. It is particularly beneficial for the treatment of diabetes, impaired glucose tolerance, and diabetic complication. It also reduces the blood sugar level by acting on cold cells to increase insulin secretion, so it is better for the treatment of diabetes and glucose tolerance abnormalities. Examples of the activity inhibitor of S G L Τ 2 include τ 丨〇 95 5 and Japanese Patent Laid-Open No. 8 312 ΧΡ / invention specification (supplement) / 94-〇7/94106583 1351400

1 0 - 2 3 7 0 8 9號、日本專利特開2 0 0 1 - 2 8 8 1 7 8號、國際公開公報W Ο Ο 1 / 1 6 1 4 7號、國際公開公報W Ο Ο 1 / 2 7 1 2 8號、國際公開公報WO Ο 1 / 6 8 6 6 0號、國際公開公報WO Ο 1 / 7 4 8 3 4號、國際公開公報W001/74835號、國際公開公報W002/28872 號、國際公開公報 W00 2/ 3 6 6 0 2 號、國際公開公報 W 0 0 2 / 4 4 1 9 2號、國際公開公報W 0 0 2 / 5 3 5 7 3號、國際公開公報W 0 0 3 / 0 0 0 7 1 2號、國際公開公報W 0 0 3 / 0 2 0 7 3 7號等記載之化合物。S G L T 2活性抑制劑特別適合於糖尿病、葡萄糖耐性異常、糖尿病性併發症、肥胖症、高胰島素血症等之治療，同時由於能夠抑制腎臟泌尿小管中葡萄糖再吸收而減低血糖值，故對糖尿病、葡萄糖耐性異常 '肥胖症、高胰島素血症之治療更好。胰島素或胰島素類似物可列舉如人體胰島素、動物來源胰島素、人體或動物來源胰島素類似物等。此等藥劑特別有利於治療糖尿病、葡萄糖耐性異常、糖尿病性併發症，同時對糖尿病、葡萄糖耐性異常之治療更好。升糖素受體拮抗劑可列舉如 B A Y - 2 7 - 9 9 5 5 、 NNC - 92 - 1 6 8 7 等，胰島素受體激酶刺激劑可列舉如 TER - 17411 ' L - 783281、KRX-613 等，三肽酶 II 抑制劑可列舉如 U C L - 1 3 9 7 等，二肽酶 I V 抑制劑可列舉如 NVP - DPP728A' TSL - 225、P - 32/98 等；蛋白質酿胺酸填酸酶 1 B 抑制劑可列舉如 P T P - 1 1 2 、 0 C - 8 6 8 3 9、 PNU - 177496 等，肝醣磷酸化酶抑制劑可列舉如 N N - 4 2 0 1、C P - 3 6 8 2 9 6等，果糖二磷酸酶抑制劑可列舉如 312XP/發明說明書(補件)/94-07/94106583 62 ⑧ 13514001 0 - 2 3 7 0 8 9 , Japanese Patent Laid-Open No. 2 0 0 1 - 2 8 8 1 7 8 , International Gazette W Ο Ο 1 / 1 6 1 4 7 , International Gazette W Ο Ο 1 / 2 7 1 2 8 , International Gazette WO Ο 1 / 6 8 6 6 0, International Gazette WO Ο 1 / 7 4 8 3 4, International Publication No. W001/74835, International Publication Bulletin W002/28872 No., International Publication No. W00 2/3 6 6 0 2, International Gazette W 0 0 2 / 4 4 1 9 2, International Gazette W 0 0 2 / 5 3 5 7 3, International Publication Bulletin WO Compounds described in No. 0 3 / 0 0 0 7 1 2, International Gazette W 0 0 3 / 0 2 0 7 3 . SGLT 2 activity inhibitor is especially suitable for the treatment of diabetes, glucose tolerance, diabetic complications, obesity, hyperinsulinemia, etc., and at the same time, it can reduce the blood sugar level by inhibiting glucose reabsorption in the renal urinary tubules. Abnormal glucose tolerance is better for the treatment of obesity and hyperinsulinemia. The insulin or insulin analog may, for example, be human insulin, animal-derived insulin, human or animal-derived insulin analog or the like. These agents are particularly useful for the treatment of diabetes, impaired glucose tolerance, and diabetic complications, as well as better treatment for diabetes and impaired glucose tolerance. The glycoside receptor antagonist may, for example, be BAY - 2 7 - 9 9 5 5 , NNC - 92 - 1 6 8 7 or the like, and the insulin receptor kinase stimulating agent may, for example, be TER - 17411 ' L - 783281, KRX-613 Etc., the tripeptidase II inhibitor may, for example, be UCL-1339 or the like, and the dipeptidase IV inhibitor may, for example, be NVP-DPP728A' TSL-225, P-32/98, etc.; protein tyrosine acid hydratase The 1 B inhibitor may, for example, be PTP - 1 1 2 , 0 C - 8 6 8 3 9 , PNU - 177496 or the like, and the heganose phosphorylase inhibitor may, for example, be NN - 4 2 0 1 or CP - 3 6 8 2 9 6 et al, fructose diphosphatase inhibitors can be cited as 312XP / invention instructions (supplement) /94-07/94106583 62 8 1351400

R - 132917等，丙酮酸去氫酶抑制劑可列舉如 AZD - 7545 等，肝醣新生抑制劑可列舉如FR - 225659等，升糖素樣胜肽-1類似物可列舉如易希定（exendin - 4)、CJC - 1131 等1升糖素樣胜肽-1 促效劑可列舉如 AZM-134' LY - 315902等，香樹素、香樹素類似物及香樹素促效劑可列舉如醋酸普拉林替（pramlintide acetate)等。以上各藥劑及葡萄糖-6 -磷酸酶抑制劑、D -手肌醇、肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1等特別有利於治療糖尿病、葡萄糖耐性異常、糖尿病性併發症 '高胰島素血症，同時對糖尿病、葡萄糖耐性異常之治療更好。醛糖還原酶抑制劑可列舉如抗壞血酸加莫利酸 (ascorbyl gamolenate)、托爾司他（tolrestat)、依帕司他(epalrestat)、ADN - 138、BAL- ARI8 ' ZD - 5 5 2 2、 ADN - 3 11' GP - 1447、 I DD - 598、菲達司他（fidarestat)、索維尼（sorbinil)、祐拿司他（ponalrestat)、利沙司他 (risarestat)、善那司他（zenarestat)、米那司他 (minalrestat) ' 甲索維尼（methosorbinil)、AL - 1567、伊米司他（imirestat)、 Μ- 16209、 TAT、 AD- 5467、佐伯司他(zopolrestat) 、 AS- 3 2 0 1 、 N Z- 314 、 SG - 210 、 JTT - 811、林多司他（lindolrestat)等。醛糖還原酶抑制劑由於能夠抑制醛糖還原酶，使在糖尿病性併發症組織發生持績性高血糖狀態之聚醇代謝途徑亢進而降低過剩蓄積之細胞内山梨糖醇濃度，故特別有利於糖尿病性併發症之治療。 63⑧ 312XP/發明說明書(補件)/94-07/94106583R-132917 and the like, the pyruvate dehydrogenase inhibitor may, for example, be AZD-7545, and the hepatic sugar stimulating inhibitor may be exemplified by FR-225659 or the like, and the glycoside-like peptide-1 analog may be exemplified by Yixiding ( Exendin - 4), CJC-1131 and other 1 liters of glycopeptide-1 agonist can be enumerated as AZM-134' LY - 315902, etc., fragrant tree, fragrant tree analog and auxin agonist For example, pramlintide acetate and the like are listed. Each of the above agents, glucose-6-phosphatase inhibitor, D-hand inositol, glycogen synthase kinase-3 inhibitor, and glycoside-like peptide-1 are particularly beneficial for the treatment of diabetes, glucose tolerance, and diabetes. Complications of 'hyperinsulinemia, and better treatment of diabetes, glucose tolerance abnormalities. The aldose reductase inhibitor may, for example, be ascorbyl gamolenate, tolrestat, epalrestat, ADN-138, BAL-ARI8 'ZD-5 5 2 2. ADN - 3 11' GP - 1447, I DD - 598, fidarestat, sorbinil, ponalrestat, risarestat, zenarestat, Minarrestat 'methosorbinil, AL-1567, imirestat, Μ-16209, TAT, AD-5467, zopolrestat, AS-3 2 0 1 , N Z- 314 , SG - 210 , JTT - 811 , lindolrestat , etc. An aldose reductase inhibitor is particularly advantageous because it inhibits aldose reductase and causes a metabolic pathway of a hyperglycemia in a diabetic complication to reduce the concentration of sorbitol in the excess accumulation. Treatment of diabetic complications. 638 312XP / invention manual (supplement) /94-07/94106583

1351400 後期糖化最終產物生啟抑制劑如比哆 (pyridoxamine)' 0ΡΒ- 9195、 ALT- 946、 ALT- 711、鹽皮馬蓋定（pimagedine HC1)等。後期糖化最終產物生成制劑由於能夠抑制在糖尿病狀態下因持續性高血糖而亢之後期糖化最終產物的生成，藉此減輕細胞障礙，故特有利於糖尿病性併發症之治療。蛋白質激酶C抑制劑可列舉如L Y - 3 3 3 5 3 1、米度斯塔 (m i d 〇 s t a u r i η )等。蛋白質激酶C抑制劑由於能夠抑制在尿病狀態因持續性高血糖而亢進之蛋白質激酶C的活性故特別有利於糖尿病性併發症之治療。 Τ - 胺基丁酸受體拮抗劑可列舉如多必拉 (topiramate)，納離子通道#抗劑可列舉如鹽酸美西 (mexiletine HC1)、氧溴隱亭（oxcarbazepin)等，轉錄子N F - /c B抑制劑可列舉如得力寶丹（d e X 1 i ρ 〇 t a m )等，質過氧化酶抑制劑可列舉如曱磺酸替利拉撤（t i r i 1 a z m e s y 1 a ΐ e )等，/V -乙酿化-a -連結酸性二肽酶抑制劑列舉如 G P I - 5 6 9 3 等，肉鹼衍生物可列舉如肉 (carnitine)、鹽酸左旋西卡敏（levacecarnine HC1)、 4匕左旋肉給(levocarnitine chloride)、左旋肉 (levocarnitine)、ST - 261等。以上各藥劑及膝島素樣長因子-I、血小板來源生長因子、血小板來源生長因子似物、上皮增殖因子、神經生長因子、尿核苷、5 ^ -經基-1 曱基乙内醯脲、E G B - 7 6 1、必莫克默、舒得塞、Y - 1 2 8 特別有利於糖尿病性併發症之治療。 312XP/發明說明書(補件)/94-07/94 ] 06583 胺酸抑進別林糖 > 美律因脂 ad 可驗氣驗生類等 64⑧ l35l4〇〇止瀉劑或瀉劑可列舉如聚卡波菲爾飼（P ο 1 y c a r b 〇 p h i 1 C a )、鞣酸蛋白、次硝酸鉍等。此等藥劑特別有利於伴隨糖展病等之下痛i、便秘等之治療。1351400 Late glycation end products such as pyridoxamine ' 0ΡΒ-9195, ALT- 946, ALT-711, pimagedine HC1 and so on. The late glycation end product production preparation is particularly advantageous for the treatment of diabetic complications because it can inhibit the formation of a final glycation end product due to persistent hyperglycemia in a diabetic state, thereby alleviating cellular disorders. The protein kinase C inhibitor may, for example, be L Y - 3 3 3 5 3 1 or mitta (m i d 〇 s t a u r i η ). The protein kinase C inhibitor is particularly advantageous for the treatment of diabetic complications because it inhibits the activity of protein kinase C which is hyperactive due to persistent hyperglycemia in the urinary state. The Τ-aminobutyric acid receptor antagonist may, for example, be a topiramate, and the nano-ion channel #anti-agent may, for example, be mexiletine HCl, oxcarbazepin, or the like, transcript NF- Examples of the /c B inhibitor include de X 1 i ρ 〇 tam, and the peroxidase inhibitor may be, for example, tiri 1 azmesy 1 a ΐ e or the like. The V-B-stabilized-a-linked acidic dipeptidase inhibitors are exemplified by GPI - 5 6 9 3 and the like, and the carnitine derivatives may be exemplified by carnitine, levacecarnine HCl, 4 lev. Levocarnitine chloride, levocarnitine, ST-261, etc. Each of the above agents and ankylosin-like long-factor-1, platelet-derived growth factor, platelet-derived growth factor-like substance, epithelial growth factor, nerve growth factor, urinary nucleoside, 5^-radio-1 mercaptoin , EGB - 7 6 1, Bimomo, Shu Desai, Y - 1 2 8 is particularly beneficial for the treatment of diabetic complications. 312XP/Inventive Manual (supplement)/94-07/94] 06583 Amino acid inhibits Belin sugar> Melody can be used for gas test and other 648 l35l4 〇〇 antidiarrheal or laxatives can be listed as Capofil feed (P ο 1 ycarb 〇phi 1 C a ), citrate protein, bismuth subnitrate, and the like. These agents are particularly advantageous for the treatment of pain i, constipation, etc., accompanied by a glycemic disease.

羥甲基戊二醯基酶A還原酶抑制劑可列舉如西里瓦司他丁（serivastatin Na)、普拉伐他丁納（pravastatin Na)、洛伐他丁（lovastatin)、欣伐他丁（simvastatin)、氟伐他丁鋼(fluvastatin Na)、阿托伐他丁 (atorvastatin Ca-trihydrate)、SC- 4 5 3 5 5 ' SQ - 3 3 6 0 0、CP- 83101 ' BB - 476、L - 669262、S - 2468、DMP - 565、U - 20685、 BAY - x - 2 6 7 8 、 BAY - 1 0 - 29 8 7 、必他伐他丁鈣 (Pitavastatin Ca)、樂施伐他丁約（rosuvastatin Ca)' 可列史特隆（colestolone)、達伐他丁（dalvastatin)、阿昔達美（acitemate)、美伐他丁（mevastatin)、克利伐他丁 (crilvastatin)、 BMS- 180431' BMY- 21950、格林伐他丁 (glenvastatin)、卡伐他丁（carvastatin)、 BMY- 22089、 ^ 巴伐他丁（bervastatin)等。經曱基戊二基輔酶A還原酶抑制劑特別有利於治療高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常、動脈粥樣硬化症，並由於能夠抑制羥甲基戊二基輔酶A還原酶而使血中膽固醇降低，故更適合高脂血症、高膽固醇血症、動脈粥樣硬化症之治療。 -- 纖維酸（f i b r a t e )衍生物可列舉如必降脂 . (bezafibrate) ' 倍氯貝特（beclobrate)、必寧貝特 (binifibrate)、環丙貝特（ciprofibrate)、可麗諾貝特 (clinofibrate) ' 氣貝特（clofibrate) 、 ί呂氣貝特 312ΧΡ/發明說明書(補件)/94_07/94丨06583 65 ⑧ 1351400The hydroxymethylpentadienyl A reductase inhibitor may, for example, be serivastatin Na, pravastatin Na, lovastatin, simvastatin ( Simvastatin), fluvastatin Na, atorvastatin Ca-trihydrate, SC-4 5 3 5 5 ' SQ - 3 3 60 0, CP- 83101 ' BB - 476, L - 669262, S - 2468, DMP - 565, U - 20685, BAY - x - 2 6 7 8 , BAY - 1 0 - 29 8 7 , Pitavastatin Ca, Levastatin Ca (rosuvastatin Ca)' Colestolone, dalvastatin, acitemate, mevastatin, crevastatin, BMS- 180431' BMY-21950, glivastatin, carvastatin, BMY-22089, bulvastatin, and the like. The thioglycoside-Kyrease A reductase inhibitor is particularly beneficial for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis, and the ability to inhibit methylol It is more suitable for the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis. -- Fibrate derivatives can be listed as fat-reducing. (bezafibrate) 'beclobrate, binifibrate, ciprofibrate, colainobet ( Clinofibrate) 'clofibrate', ί吕气贝特312ΧΡ/invention manual (supplement)/94_07/94丨06583 65 8 1351400

(clofibrate Al)、氯纖維酸（clofibric acid)、易得貝特 (etofibrate)、非諾貝特（fenofibrate)、健菲布脂 (gemfibrate)、尼可貝特（nicofibrate)、必利貝特 (pirifibrate)、樂你貝特（ronifibrate)、新貝特 (simfibrate)' 茶貝特（theofibrate)' AHL- 157 等。纖維酸系化合物特別有利於治療高胰島素血症、高脂血症、高膽固醇血症、高三酸甘油脂血症 '脂肪代謝異常、動脈粥樣硬化症，並由於在肝臟活化脂蛋白脂酶及促進脂肪酸氧化以降低血中三酸甘油脂，故更適合高脂血症、高三酸甘油脂血症、動脈粥樣硬化症之治療。冷3 -腎上腺素受體促效劑可列舉如 B R L - 2 8 4 1 0、 SR - 5 8 6 1 1 A ' ICI - 1 9 8 1 5 7、ZD - 2 0 7 9、BMS- 1 9 44 4 9、 BRL - 3 7 3 4 4、CP - 3 3 1 6 7 9、CP- 1 1 4 2 7 1、L- 7 5 0 3 5 5 ' BMS - 187413、SR - 59062A、BMS - 210285、LY - 377604、 SWR - 0 3 4 2 SA 、 AZ - 4 0 1 4 0 、 SB - 2 2 6 5 5 2 、 D - 7 114 、 BRL - 3 5 135、FR - 149175、BRL - 26830A、CL - 316243、 AJ - 9677、GW - 427353、N - 5984、GW - 2696、YM178 等。 Θ 3 -腎上腺素受體促效劑特別有利於治療肥胖症、高胰島素血症、高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常，並由於剌激脂肪沒3 -腎上腺素受體而促進脂肪酸氧化以消耗熱能，故更適合肥胖症、高胰島素血症之治療。醯基輔酶 A :膽固醇醯基轉移酶抑制劑可列舉如 ΝΤΕ - 122 、 MCC- 147 、 PD - 1 3 2 3 0 1 - 2 、 DUP - 129 、 312ΧΡ/發明說明書(補件)/94-〇7/941065 83 66 ⑧ 1351400(clofibrate Al), clofibric acid, etofibrate, fenofibrate, gemfibrate, nicofibrate, bilibit ( Pirififrate), ronifibrate, simfibrate 'theofibrate' AHL-157, etc. Fibrous acid compounds are particularly beneficial for the treatment of hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis, and activation of lipoprotein lipase in the liver. It promotes the oxidation of fatty acids to lower the triglyceride in the blood, so it is more suitable for the treatment of hyperlipidemia, hypertriglyceridemia and atherosclerosis. Examples of cold 3-adrenergic receptor agonists include BRL - 2 8 4 1 0, SR - 5 8 6 1 1 A ' ICI - 1 9 8 1 5 7 , ZD - 2 0 7 9 , BMS- 1 9 44 4 9, BRL - 3 7 3 4 4, CP - 3 3 1 6 7 9, CP- 1 1 4 2 7 1 , L- 7 5 0 3 5 5 ' BMS - 187413, SR - 59062A, BMS - 210285 , LY - 377604, SWR - 0 3 4 2 SA , AZ - 4 0 1 4 0 , SB - 2 2 6 5 5 2 , D - 7 114 , BRL - 3 5 135, FR - 149175, BRL - 26830A, CL - 316243, AJ-9677, GW-427353, N-5984, GW-2696, YM178, etc. Θ 3 - adrenergic receptor agonist is particularly beneficial for the treatment of obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, and due to stimulating fat - Adrenergic receptors promote fatty acid oxidation to consume heat, so it is more suitable for the treatment of obesity and hyperinsulinemia.醯Kymase A: A cholesterol thiol transferase inhibitor can be exemplified by ΝΤΕ-122, MCC-147, PD-1 3 2 3 0 1 - 2 , DUP-129, 312ΧΡ/invention specification (supplement)/94-〇 7/941065 83 66 8 1351400

U- 73482' U- 76807' RP- 70676、 P- 06139、 CP- 113818、 RP- 7 3 1 6 3 ' FR - 129169、FY - 038、EAB - 309、KY - 455、 LS- 3115、FR - 145237、T - 2591、J - 104127、R - 755、 FCE_ 28654 、 Y1C- C8_ 434 、阿伐西米（avasimibe)、 Cl - 9 7 6 ' RP - 6 4 4 7 7 ' F - 1394、易達西米（eldacimibe)、 CS- 505、CL - 283546、YM - 17E、力西米（lecimibede)、 447C88、 YM- 750、 E- 5324、 KW- 3033、 HL- 004、易福西米（e f 1 u c i m i b e )等。醯基輔酶 A :膽固醇醯基轉移酶抑制劑特別有利於治療高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常，並由於能夠抑制醯基輔酶 A :膽固醇醯基轉移酶以降低血中膽固醇，故更適合高脂血症、高膽固醇血症之治療。甲狀腺荷爾蒙受體促效劑可列舉如三碘曱腺胺酸鈉 (1 iothyronine Na)、左旋曱狀腺素納(levothyroxine Na) > KB - 26 11等，膽固醇吸收抑制劑可列舉如易希替米 (ezetimibe)'SCH - 48461，脂酶抑制劑可列舉如歐力司他 (oristat)、ATL - 962、AZM - 131、RED - 103004 等，肉驗棕櫊醯基轉移酶抑制劑可列舉如依托莫西（e t 〇 m ο X i r )等，鯊烯合成酶抑制劑可列舉如 S D Z - 2 6 8 - 1 9 8 、 BMS - 1 8 8 4 9 4、A - 8 7 0 4 9、RPR - 10 1821 、ZD- 9 7 2 0、 RPR- 107393、 ER- 27856、 TAK- 475 等，菸鹼酸衍生物可列舉如菸鹼酸、菸鹼醞胺、菸酸環己醇酯（N i c o m ο 1 )、菸酸戊四醇SI (Niceritrol)、阿西莫司（acipimox)、尼可地爾（n i c 〇 r a π d i 1 )等’膽汁酸吸附劑可列舉如膽笨稀胺 312XP/發明說明書(補件)/94-07/94106583 67 ⑧ 1351400 (cholestyramine)、固樂司替蘭（colestilan)、鹽酸固樂西維蘭（colesevelam HC1)、 GT- 102- 279 等，鈉共軛膽汁酸轉移因子抑制劑可列舉如2 6 4 W 9 4、S - 8 9 2 1、S D - 5 6 1 3 等，膽固醇酯轉移蛋白抑制劑可列舉如 P N U - 1 0 7 3 6 8 E ' SC - 795、JTT - 705、CP - 529414 等。以上各藥劑及丙丁酚、微粒體三酸甘油脂轉移蛋白質抑制劑、脂肪加氧酶抑制劑、低比重脂蛋白受體增強劑等特別有利於治療高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常。U- 73482' U- 76807' RP- 70676, P- 06139, CP-113818, RP- 7 3 1 6 3 ' FR - 129169, FY-038, EAB-309, KY-455, LS- 3115, FR - 145237, T-2591, J-104127, R-755, FCE_ 28654, Y1C-C8_434, avasimibe, Cl - 9 7 6 ' RP - 6 4 4 7 7 ' F - 1394, Easy Access Eldacimibe, CS-505, CL-283546, YM-17E, Lecimibede, 447C88, YM-750, E- 5324, KW-3033, HL-004, ef 1 ucimibe )Wait.醯Kyethase A: cholesterol thiol transferase inhibitor is particularly beneficial for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, and because it can inhibit 醯Kyethase A: cholesterol thiol transfer Enzymes are used to lower blood cholesterol, so it is more suitable for the treatment of hyperlipidemia and hypercholesterolemia. The thyroid hormone receptor agonist may, for example, be iothyronine Na, levothyroxine Na < KB - 26 11 , etc., and the cholesterol absorption inhibitor may be exemplified by Yi Xi Ezetimibe 'SCH - 48461, lipase inhibitors such as oristat, ATL - 962, AZM - 131, RED - 103004, etc. For example, et 〇m ο X ir, etc., squalene synthetase inhibitors can be exemplified by SDZ - 2 6 8 - 1 9 8 , BMS - 1 8 8 4 9 4, A - 8 7 0 4 9 RPR - 10 1821 , ZD- 9 7 2 0, RPR-107393, ER- 27856, TAK-475, etc., and nicotinic acid derivatives may, for example, be nicotinic acid, nicotinamide or cyclohexanol nicotinate (N) Icom ο 1 ), Nicotritol, acipimox, nic 〇ra π di 1 , etc. 'Bile acid adsorbents can be cited as cholesteric amine 312XP/ Description of the invention (supplement) /94-07/94106583 67 8 1351400 (cholestyramine), colestilan, colesevelam HC1, GT-102-2 79, etc., the sodium conjugated bile acid transfer factor inhibitor may be exemplified by 2 6 4 W 9 4 , S - 8 9 2 1 , SD - 5 6 1 3 , etc., and the cholesterol ester transfer protein inhibitor may be enumerated as PNU - 1 0 7 3 6 8 E 'SC-795, JTT-705, CP-529414, etc. Each of the above agents and probucol, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, low-density lipoprotein receptor enhancer, etc. are particularly beneficial for the treatment of hyperlipidemia, hypercholesterolemia, and triglyceride Glycerolemia, abnormal fat metabolism.

食慾抑制劑可列舉如一元胺再吸收抑制劑、血清素再吸收抑制劑、血清素釋放剌激劑、血清素促效劑（尤其5 Η T 2 c -促效劑）、去甲腎上腺素再吸收抑制劑、去甲腎上腺素釋放剌激劑、α，-腎上腺素受體促效劑、冷2 -腎上腺素受體促效劑、多巴胺促效劑、大麻素（c a η n a b i η 〇 i d )受體拮抗劑、r -胺基丁酸受體拮抗劑、Η 3 -組織胺受體拮抗劑、L -組胺酸、萊普亭（1 e p t i n e )、萊普亭類似物、萊普亭受體促效劑、黑皮質素（M e 1 a η 〇 c a r t i η )受體促效劑（尤其M C 3 - R 促效劑、M C 4 - R促效劑）、α -黑色素細胞刺激荷爾蒙、古柯鹼及安非他命調節轉錄物、桃花心木蛋白質、腸抑制素促效劑、抑鈣素、抑鈣素基因相關胜肽、蛙皮素 (bombesin)、縮膽囊素促效劑（尤其C C K - A促效劑）、皮促素釋放荷爾蒙、皮促素釋放荷爾蒙類似物、皮促素釋放荷爾蒙促效劑、展皮質素（u r 〇 c 〇 r t i η )、體抑素、體抑素類似物、體抑素受體促效劑、垂體腺苷酸環化酶活性化胜肽、腦來源神經生長因子、睫狀神經營養因子（c i 1 i a 1 y 312XP/發明說明書(補件)/94-07/94106583 68 ⑧ 1351400 neutrophic factor)、促甲狀腺激素釋放荷爾蒙、神經調壓素、舒巴淨（sauvagine)、神經肽 Y拮抗劑、鸦片胜肽 (〇 p i 〇 i d p e p t i d e )拮抗劑、甘丙胺素括抗劑、黑色素濃縮 _ 荷爾蒙受體拮抗劑、刺鼠（a g 〇 u t i )相關蛋白質抑制劑、阿來新（orexin)受體拮抗劑等。具體而言，一元胺再吸收抑制劑可列舉如馬淨多（m a z i n d ο I )等，血清素再吸收抑制劑可列舉如鹽酸右芬氟拉明（dexfenfluramine HC1)'芬氟拉明（fenfluramine)、鹽酸西布得拉明（sibutramine ^ HC1)、順丁稀二酸氟戊肪胺（fluvoxamine maleate)、鹽酸血得林（s e r t r a 1 i n e H C 1 )等，jk清素促效劑可列舉如伊諾得利普丹（inotriptan)、諾芬氟拉明 ((+ )norfenfluramine)等，去曱腎上腺素再吸收抑制劑可列舉如丁普羅比恩（bupropione)、GW - 320659等，去甲腎上腺素釋放剌激劑可列舉如樂利普蘭（r ο 1 i p r a m )、Y Μ - 9 9 2 等，yS2 -腎上腺素受體促效劑可列舉如安非他命、右旋安非他命、芬他命（phentermine)、曱苯異丙胺 Φ . (benzphetamine)、甲基安非他命、二苯甲嗎、苯甲嗎、雙乙基四（diethylpropion)、去曱麻黃鹼 (phenylpropanolamine)、氣苄佐樂（c1〇be πzorex )等，多巴胺促效劑可列舉如 ER- 230、多普利辛（doprexin)、甲磺酸溴隱亭（bromocriptine mesylate)等，木麻素受體拮抗劑可列舉如利莫那邦（r i m ο n a b a n t )等，7 _胺基丁酸受體拮抗劑可列舉如多必拉美（t o p i r a m a t e )等，Η 3 -組織胺受體拮抗劑可列舉如 G Τ - 2 3 9 4等，萊普亭、萊普亭類似 312ΧΡ/發明說明書(補件)/94-07/94106583 69 ⑧ 1351400 物、萊普亭受體促效劑可列舉如LY - 355101等，縮膽囊素促效劑（尤其 CCK - A促效劑）可列舉如 SR - 146131、 - SSR - 1 2 5 1 8 0、BP - 3.2 0 0、A - 7 1 6 2 3 、FPL - 1 5 84 9、 _ G I - 248573、GW - 7178、GI - 181771、GW - 7854、A - 71378 等，神經肽 Y 拮抗劑可列舉如 S R - 1 2 0 8 1 9 - A 、 PD - 160170、NGD- 95 - 1、BIBP - 3226、1 2 2 9 - U- 91、 CGP - 7 1 6 8 3、BIBO- 3304、CP - 6 7 1 9 0 6 - 01、J - 115814 等。食慾抑制劑特別有利於治療糖尿病、葡萄糖耐性異常、 Φ 糖尿病性併發症、肥胖症、高脂血症、高膽固醇血症、高三酸甘油脂血症、脂肪代謝異常、動脈粥樣硬化症、高血壓、鬱血性心竭、浮腫、高尿酸血症、痛風等，並由於在中樞.貪慾調節系中促進或抑制腦内一元胺及生理活性胜肽之作用以抑制食慾、減少能量之攝取，故更適合肥胖症之治療。Appetite suppressants include, for example, monoamine reuptake inhibitors, serotonin reuptake inhibitors, serotonin stimulating agents, serotonin agonists (especially 5 Η T 2 c - agonists), norepinephrine Absorption inhibitor, norepinephrine release stimulant, alpha, adrenergic receptor agonist, cold 2-adrenergic receptor agonist, dopamine agonist, cannabinoid (ca η nabi η 〇id ) Receptor antagonists, r-aminobutyric acid receptor antagonists, Η3-hisamine receptor antagonists, L-histamine, leptine, leptin analogues, leptin Bulk agonist, melanocortin (M e 1 a η 〇carti η ) receptor agonist (especially MC 3 - R agonist, MC 4 - R agonist), α-melanocyte stimulating hormone, ancient Keline and amphetamine-regulated transcripts, mahogany protein, enterostatin agonist, calcitonin, calcitonin gene-related peptide, bombesin, cholecystokinin agonist (especially CCK-A Agonist), dermatin releasing hormone, dermatin releasing hormone analogue, dermatotropin releasing Ergonomic agonist, ur 〇c 〇rti η, somatostatin, somatostatin analogue, somatostatin receptor agonist, pituitary adenylate cyclase active peptide, brain Source nerve growth factor, ciliary neurotrophic factor (ci 1 ia 1 y 312XP / invention specification (supplement) /94-07/94106583 68 8 1351400 neutrophic factor), thyroid stimulating hormone releasing hormone, neuromodulin, suba Sauvagine, neuropeptide Y antagonist, opiate peptide (〇pi 〇idpeptide) antagonist, alanine inhibitor, melanin concentration _ hormone receptor antagonist, ag 〇uti related protein inhibitor , orexin receptor antagonists, and the like. Specifically, the monoamine reuptake inhibitor may be exemplified by mazind ο I or the like, and the serotonin reuptake inhibitor may, for example, be dexfenfluramine HC1 fenfluramine. , sibutramine hydrochloride (HC1), fluvoxamine maleate (fluvoxamine maleate), sertra 1 ine HC 1 , etc., jk clear agonist can be listed as Nodriptan, nofenfluramine, etc., and norepinephrine reuptake inhibitors such as bupropione, GW-320659, etc., norepinephrine Examples of the release stimulating agent include r lympson (r ο 1 ipram ), Y Μ - 9 9 2 and the like, and yS2-adrenergic receptor agonist may, for example, be amphetamine, dextroamphetamine, phentermine, Amphetamine Φ. (benzphetamine), methamphetamine, benzophenone, benzophenone, diethylpropion, phenylpropanolamine, c1〇be πzorex Wait, more The amine agonist may, for example, be ER-230, doprexin, bromocriptine mesylate or the like, and the cinnamic receptor antagonist may be exemplified by rim ο nabant. The 7-aminobutyric acid receptor antagonist may, for example, be topiramate or the like, and the Η3-historamine receptor antagonist may, for example, G Τ - 2 3 9 4, etc., Leptin, Lepu Kiosk similar to 312 ΧΡ / invention instructions (supplement) / 94-07/94106583 69 8 1351400, leptin receptor agonist can be listed as LY-355101, etc., cholecystokinin agonist (especially CCK-A efficacious The agent can be exemplified by SR - 146131, - SSR - 1 2 5 1 8 0, BP - 3.2 0 0, A - 7 1 6 2 3 , FPL - 1 5 84 9 , _ GI - 248573, GW - 7178, GI - 181771, GW-7854, A-71378, etc., and neuropeptide Y antagonists may, for example, be SR - 1 2 0 8 1 9 - A , PD - 160170, NGD-95 - 1, BIBP - 3226, 1 2 2 9 - U-91, CGP-7 1 6 8 3, BIBO-3304, CP-6 7 1 9 0 6 - 01, J-115814, etc. Appetite suppressants are particularly beneficial for the treatment of diabetes, impaired glucose tolerance, Φ diabetic complications, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis, high Blood pressure, septic depletion, edema, hyperuricemia, gout, etc., and promote or inhibit the action of monoamines and physiologically active peptides in the brain to suppress appetite and reduce energy intake. Therefore, it is more suitable for the treatment of obesity.

血管升壓素轉移酶抑制劑可列舉如卡托普利 (c a p t 〇 p r i 1 )、順丁燁二酸恩納普利（e n a 1 a p r i 1 maleate)、阿拉西普利（alacepril)、鹽酸得拉普利 (delapril HC1)、雷米普利（ramipril)、賴諾普利 (lisinopril)、咪0坐普利（imidapril HC1)、鹽酸洛丁新片 (benazepril HC1) ' 西樂那普利水合物（seronapril hydrate )、西拉查普利（cilazapril)、福西諾普利鈉 (fosinopril Na) ' 皮林多普利（perindopril)、莫弗地普利奸（moveltipril calcium)、鹽酸基那普利（quinapril H C 1 )、鹽酸螺旋普利（s p i r a p r i 1 H C 1 )、鹽酸替莫卡普利 312XP/發明說明書(補件)/94·07/94106583 70 ⑧ 1351400 (temocapr i1 HC1)、都蘭多普利（trandolapril)、佐芬普 M 1¾ (calcium zofenopril) ' 鹽酸莫西普利（moexipril)、樂替普利（r e n t i a p r i 1 )等。血管升壓素轉移酶抑制劑特別有利於治療糖尿病性併發症、高血壓。中性肽鐽内切酶抑制劑可列舉如奧馬巴得樂 (omapatrilat)、 MDL- 100240、法西度得利（fasidotril)、新巴得樂（sampatrilat) 、 GW- 660511X 、美山普利The vasopressin transferase inhibitor may, for example, be captopril (capt pri 1 ), ena 1 apri 1 maleate, aracepril (alacepril), hydrochloride rap (delalipl HC1), ramipril, lisinopril, imidapril HC1, benazepril HC1, selepapril hydrate (seronapril hydrate) ), cilazapril, fosinopril Na 'perindopril, moteltipril calcium, quinapril HC 1 ), spirapri 1 HC 1 , temocapril hydrochloride 312XP / invention instructions (supplement) /94·07/94106583 70 8 1351400 (temocapr i1 HC1), trandolapril , zofenpu M 13⁄4 (calcium zofenopril) 'moexipril hydrochloride (lortipril), lactipril (rentiapri 1) and the like. Vasopressin transferase inhibitors are particularly beneficial for the treatment of diabetic complications and hypertension. Neutral peptide endonuclease inhibitors can be enumerated, for example, omapatrilat, MDL-100240, fasidotril, sampatrilat, GW-660511X, Mesapril

(mixanpril)、SA - 7060、E - 4030、SLV - 306 ' 益加得利 (e c a d 〇 t r i 1 )等。中性肽鍵内切酶抑制劑特別有利於治療糖尿病性併發症、高血壓》血管升壓素 II受體拮抗劑可列舉如康得沙丹西利得 (candesar tan c i 1 ex e t i 1 )、康得沙丹西利得/氫氣噻唑 (candesartan cilexetil / hydrochlorothiazide)、樂沙丹 if (losarten K) ' 益普樂沙丹（eprosartan mestlate)、況沙丹（v a 1 s a r t e η )、得美沙丹（t e 1 m i s a r t a η )、益必沙丹 • (irbesarten)、EXP - 3174、L - 158809、EXP - 3312' 歐美沙丹（olmesartan)、大索沙丹（tasosartan)、 KT- 3- 671、 GA - 0 113' RU- 6427 6、EMD - 90 42 3、BR - 9 7 0 1 等。血管升壓素I I受體拮抗劑特別有利於治療糖尿病性併發症、高血壓。内皮素轉移酶抑制劑可列舉如 C G S - 3 1 4 4 7 、 CGS - 35066、SM - 19712等，内皮素受體拮抗劑可列舉如 L - 7 4 9 8 0 5 ' TBC - 3214、BMS- 1 82 8 7 4、BQ- 6 1 0 ' ΤΑ - 0 2 0 1 ' SB- 215355 、 PD- 180988 、西他仙丹（sitaxsentan)、 71 3】2XP/發明說明書(補件)/94-07/94 IO65 83 1351400 BMS - 193884、達樂仙丹（darusentan)、TBC - 3711、寶仙丹（bosentan)、替佐仙丹納（tezosentan Na)、 J - 104132 、 YM - 5 9 8 ' S- 0139 、 SB- 234 5 5 1 ' RPR - 1 1 8 0 3 1 A 、 ATZ - 1 9 9 3 、 R0 - 61- 1790 ' ABT- 546 、印拉仙丹 (enlasentan)、 BMS- 207940等。此等藥劑有利於治療糖尿病性併發症、高血壓，並特別適合於高血壓之治療。(mixanpril), SA-7060, E-4030, SLV-306 'e c a d 〇 t r i 1 ), and the like. Neutral peptide endonuclease inhibitors are particularly beneficial for the treatment of diabetic complications, hypertension. Vasopressin II receptor antagonists can be cited, for example, candesar tan ci 1 ex eti 1 Dessandan cilexetil / hydrochlorothiazide, losarten K, eprosartan mestlate, va 1 sarte η, dermatone (te 1) Misarta η ), ibbesarten, EXP - 3174, L - 158809, EXP - 3312' olmesartan, tasosartan, KT- 3-671, GA - 0 113 ' RU- 6427 6, EMD - 90 42 3, BR - 9 7 0 1 and so on. Angiotensin I I receptor antagonists are particularly advantageous for the treatment of diabetic complications, hypertension. The endothelin-transferase inhibitor may, for example, be CGS - 3 1 4 4 7 , CGS - 35066, SM - 19712, etc., and the endothelin receptor antagonist may be exemplified by L - 7 4 9 8 5 5 ' TBC - 3214, BMS- 1 82 8 7 4, BQ- 6 1 0 ' ΤΑ - 0 2 0 1 ' SB- 215355 , PD- 180988 , sitaxsentan , 71 3 ] 2XP / invention manual (supplement) /94-07/ 94 IO65 83 1351400 BMS - 193884, darusentan, TBC - 3711, bosentan, tezosentan Na, J - 104132, YM - 5 9 8 ' S- 0139 , SB- 234 5 5 1 ' RPR - 1 1 8 0 3 1 A , ATZ - 1 9 9 3 , R0 - 61- 1790 ' ABT- 546 , enlasentan (enlasentan), BMS- 207940, etc. These agents are useful for the treatment of diabetic complications, hypertension, and are particularly suitable for the treatment of hypertension.

利尿劑可列舉如氣養酮（chlorthalidone)、美多拉松 (metolazone)、環戊氣噻口序（cyclopenthiazide)、三氣甲派0塞 D并（trichlormethiazide)、氫氯嗟喷（hydrochlorothiazide)、氫氟。塞 °并（hydrof lumethiazide)、节氫氯嘆。片（benzylhydrochlorothiazide) 、五氟替0i (penflutizide)、曱氣。塞0井（methyclothiazide)、0弓 I 達胺（indapamide)、麴帕胺（tripamide)、阿佐 °塞米（azosemide)、益他克力寧酸（ethacrynicacid)、多拉西邁（torasemide)、0比0各他尼（piretanide)、呋噻米（furosemide) 、丁尿胺 (bumetamide)、美地克余（meticrane)、康樂酸钟（potassium canrenoate) 螺内醋（spironolactone)、氨苯蝶咬 (triamterene)、胺苯驗（amiinophyline )、鹽酸喜克力他寧 (cicletanine HC1) 、 LLU- a ' PNU- 80873A 、異山梨酯 (i sosorbide)、D -甘露醇、D -山梨糖醇、果糖、甘油、乙醯唑胺（acetazolamide)、美他佐拉邁（metazolamide)、FR - 179544、 0PC - 31260、力善伐丹（lixivaptan)、鹽酸可尼伐丹（conivaptan HC1 )等。利尿劑有利於治療糖尿病性併發症、高血壓、鬱血性心竭、浮腫等，並由於增加排尿量以降低血壓 '改善浮腫，故特別適合於高血壓、鬱血性心竭、浮腫之治療。 ⑧ 312XP/發明說明書(補件)/9^07/94106583 1351400Diuretics may, for example, be chlorthalidone, metolazone, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, Hydrofluoric. Hydrof lumethiazide, hydrogen sigh. Tablet (benzylhydrochlorothiazide), pentafluent 0i (penflutizide), hernia. Meyclothiazide, indapamide, tripamide, azosemide, ethacrynic acid, torasemide, 0 More than pitanitan, furosemide, bumetamide, meticrane, potassium canrenoate, spironolactone, acetonide Triamterene), amiinophyline, cicletanine HC1, LLU- a 'PNU- 80873A, isosorbide, D-mannitol, D-sorbitol, fructose, Glycerin, acetazolamide, metazolamide, FR-179544, 0PC-31260, lixivaptan, conivaptan HC1, and the like. Diuretics are beneficial for the treatment of diabetic complications, hypertension, septic depletion, edema, etc., and because of increased urine output to lower blood pressure 'improve edema, it is especially suitable for the treatment of hypertension, stagnation of the heart and edema. 8 312XP/Invention Manual (supplement)/9^07/94106583 1351400

鈣離子拮抗劑可列舉如阿拉尼地平（a r a n i d i p i n e )、鹽酸益福尼地平（efonidipine HC1)、鹽酸尼卡迪平 (nicardipine HC1)、鹽酸巴尼地平（barnidipine HC1)' 鹽酸必尼地平（benidipine HC1)、鹽酸馬尼地平 (manidipineHCl)、喜爾尼地平（cilnidipine)' 尼索地平 (nisoldipine) ' 尼川迪（nitrendipine)、尼弗地平 (nifedipine) ' 尼伐地平（nilvadipine)、費樂地平 (felodipine)、驗性安樂地平（amlodipine basylate)、普拉尼地平（pranidipine)'鹽酸樂加尼地平（lercanidipine HC1)、依拉地平（isra(jipine)、益高地平（elgodipine)、阿塞爾尼地平（azelnidipine)、樂息平（lacidipine)、鹽酸伐他尼地平（vatanidipine HC1)、樂美地平 (lemildipine)、鹽酸地爾硫卓（diltiazem HC1)、順丁稀二酸可侖替善（clentiazem maleate)、鹽酸維拉帕米 (verapamil HC1)、S 維拉帕米（S-verapamil)、鹽法蘇替（fasudil HC1)、鹽酸苄丙洛（bepridil HC1)、鹽酸曱氧帕米（gal lopami 1 HC1 )等。血管擴張性降血壓劑可列舉如因0引達胺（indapamide)、鹽酸多樂拉朋 (todralazine HCI) '鹽酸海卓拉肼（hydralazine HC1)、卡樂拉朋· (cadralazine)、布駄嗓（budralazine)等。交感神經阻斷劑可列舉如鹽酸阿莫斯洛爾（amosulalol HC1)、鹽酸特拉 °坐唤（terazosin HC1)、鹽酸布那。坐唤（bunazosin HC1)、鹽酸布拉°坐°秦（p r a ζ 〇 s i η H C 1 )、甲續酸多沙°坐β秦 (doxazosin mesylate)、鹽酸普萘洛爾（propranolol ⑧ 31 ixP/發明說明書(補件)/94-07/94丨06583 1351400 HC1)、阿替洛爾（atenolol)、酒石酸美多普洛（metoprolol tartrate)、卡維地洛® (carvedilol)、尼普拉洛爾 (nipradilol)、鹽酸塞利普洛（celiprolol HC1)、尼必洛爾（nebivolol)、倍他索洛爾（betaxolol) 、 D引哚洛爾 (pindolol)、鹽酸特他洛 ®(tertatolol HC1)、鹽酸貝凡特洛爾（bevantolol HC1)、順丁稀二酸0S 嗎洛爾（timolol maleate)、鹽酸卡地洛爾（carteololHCl)、半反丁烤二酸比索洛爾（bisoprolol fumarate)、丙二酸波吲洛爾Calcium ion antagonists may, for example, be aranidipine, efonidipine HC1, nicardipine HCl, barnidipine HCl, benidipine hydrochloride (benidipine HC1) Manidipine HCl, cilnidipine 'nisoldipine' nitrendipine, nifedipine 'nilvadipine, felodipine ( Felodipine), amlodipine basylate, pranidipine 'lercanidipine HC1', erradipine (ispine), isra (jipine), elgodipine (elgodipine), acerney Azelnidipine, lacidipine, vatatanidipine HC1, lemildipine, diltiazem HC1, clentiazem maleate, Verapamil HC1, S-verapamil, fasudil HC1, bepridil HC1, hydrochloric acid Oxypamamine (HC lopami 1 HC1), etc. Vasodilating hypotensive agents include, for example, indapamide, todralazine HCI, hydralazine HC1, card Cadalazine, budralazine, etc. Sympathetic blockers include, for example, amosulalol HC1, terazosin HC1, and buna hydrochloride. Calling (bunazosin HC1), hydrochloric acid, sitting on the sputum, pra ζ si η HC 1 , sedative acid, doxazosin mesylate, propranolol hydrochloride, propranolol 8 31 ixP / invention Instructions (supplement) /94-07/94丨06583 1351400 HC1), atenolol, metoprolol tartrate, carvedilol, nipralorol Nipradilol), celiprolol HC1, nebivolol, betaxolol, pindolol, tertatolol HC1, hydrochloric acid Bevantolol HC1, timolol maleate , carteolol hydrochloride, bisoprolol fumarate, propofol malonate

(bopindolol malonate)、尼普拉洛爾（nipradilol)、硫酸喷布洛爾（penbutolol sulfate)、鹽酸醋丁洛爾 (acebutoIolHCl)、鹽酸替利索洛 il(tilisololHCl)、納多洛爾（n a d ο 1 ο 1 )、烏拉地爾（u r a p i d i 1 )、吲哚拉明 (indoramin)等。中柩性降血壓藥可列舉如利血平 (reserpine)。-腎上腺素受體促效劑可列舉如鹽酸可尼定（colnidine HC1)、甲基苯丙胺酸(methyldopa)、 CHF - 1 0 3 5 ' 氯笨胺胍（guanabenz acetate)、鹽酸胍.法新 (guanfacine HC1)、莫索尼定（moxonidine)、洛非西定 (lofexidine)、鹽酸他利必索（talipexole HCl)#。以上各藥劑特別適合治療高血壓。抗血小板劑可列舉如鹽酸噻氣匹定（t i c 1 ο p i d i n e HC1)、雙01 達莫（dipyridamole)、西洛斯他。坐 (cilostazol)' 二十五酸乙 fi旨（ethyl icosapentate)、鹽酸沙寶格列替（s a r p o g r e 1 a t e H C 1 )、二鹽酸地拉齊普 (dilazep 2HC1)、唑嘧胺（trapidil)、倍拉普羅斯鈉 3丨2XP/發明說明書(補件)/94-07/94106583 74 ⑧ 1351400 (b e r a p r 〇 s t N a )、阿司匹靈等。抗血小板劑特別有用於治療動脈粥樣硬化症、#血性心竭。尿酸生成抑制劑可列舉如別嘌醇（a 1 1 〇 p u r i η ο 1 )、氧普利法（ο χ y ρ u r i π ο 1 )等，尿酸排泄促進藥可列舉如苯溴馬隆 (benzbromarone)、丙項舒（probenecid)等，展驗性化劑可列舉如碳酸氫鈉、檸檬酸鉀、檸檬酸鈉等。以上各藥劑特別適合治療高尿酸血症、痛風。(bopindolol malonate), nipradilol, penbutolol sulfate, acebutoIolHCl, tilisolol HCl, nad ο 1 ο 1 ), urapidi 1 , indoramin, etc. A neutralizing blood pressure lowering drug can be exemplified by reserpine. - Adrenergic receptor agonists include, for example, coronidine HCl, methyldopa, CHF - 1 0 3 5 'guanabenz acetate, guanidine hydrochloride. Guanfacine HC1), moxonidine, lofexidine, taliexole HCl #. Each of the above agents is particularly suitable for the treatment of hypertension. The antiplatelet agent may, for example, be timolidine hydrochloride (t i c 1 ο p i d i n e HC1), di 01, dipyridamole, cilostatin. Sit (cilostazol) 'ethyl icosapentate, sarpogre 1 ate HC 1 , dilazep 2HC1, trapidil, times Lapros Sodium 3丨2XP/Invention Manual (supplement)/94-07/94106583 74 8 1351400 (berapr 〇st N a ), aspirin, etc. Antiplatelet agents are particularly useful in the treatment of atherosclerosis, #血心心. Examples of the uric acid production inhibitor include allopurinol (a 1 1 〇puri η ο 1 ), oxypril method (ο χ y ρ uri π ο 1 ), and the like, and the uric acid excretion promoting drug may be, for example, benzbromarone (benzbromarone). For example, a probenecid or the like, and examples of the exhibiting agent include sodium hydrogencarbonate, potassium citrate, sodium citrate, and the like. Each of the above agents is particularly suitable for the treatment of hyperuricemia and gout.

例如與本發明之化合物組合使用時，於治療糖尿病最好由胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶II 抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 B抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇、肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1、血糖素樣胜肽-1類似物、血糖素樣胜肽-1促效劑、香樹素、香樹素類似物、香樹素促效劑及食慾抑制劑等所構成群組中至少選取1種藥劑組合使用較好；而由胰島素敏感性增強劑 '糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑' 三肽酶II 抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 B抑制劑、肝醣磷酸化酶抑制劑、葡糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、 ⑧ 312XP/發明說明書(補件)/94-07/94106583 1351400For example, when used in combination with the compound of the present invention, it is preferred to treat diabetes by an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretion promoter, an SGLT2 activity inhibitor, an insulin or insulin analog, or a glycoside. Body antagonist, insulin receptor kinase stimulating agent, tripeptidase II inhibitor, dipeptidase IV inhibitor, protein tyrosine phosphatase 1 B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase Inhibitor, fructose diphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic glucose stimulating inhibitor, D-hand inositol, glycogen synthase kinase-3 inhibitor, glycosidic peptide-1, blood glucose At least one selected from the group consisting of the peptide-like peptide-1 analog, the glycoprotein-like peptide-1 agonist, the fragrant tree, the fragrant tree analog, the auxin agonist, and the appetite suppressant Combination of agents is better; and insulin sensitivity enhancer's sugar absorption inhibitor, biguanide, insulin secretion promoter, SGLT2 activity inhibitor, insulin or insulin analog, glycosidic receptor antagonist, insulin receptor Enzyme stimulant 'Tripeptide enzyme II inhibitor, dipeptidase IV inhibitor, protein tyrosine phosphatase 1 B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose diphosphate Enzyme inhibitor, pyruvate dehydrogenase inhibitor, hepatic sugar stimulating inhibitor, 8 312XP / invention specification (supplement) /94-07/94106583 1351400

D _手肌醇 '肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1、血糖素樣胜肽-1類似物、血糖素樣胜肽-1促效劑、香樹素、香樹素類似物及香樹素促效劑等所構成群組中至少選取1種藥劑組合使用更好；並由肤島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2 活性抑制劑及胰島素或胰島素類似物等所構成群組中至少選取1種藥劑組合使用為最好。同樣地於治療糖尿病性併發症中，由胰島素敏感性增強劑、糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶 1 B抑制劑、肝醣磷酸化酶抑制劑、葡糠-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇、肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1、血糖素樣胜肽-1 類似物、血糖素樣胜肽-1 促效劑、香樹素、香樹素類似物、香樹素促效劑、酸糖還原酶抑制劑、後期糖化最終產物生成抑制劑、蛋白質激酶C抑制劑、7 -胺基丁酸受體拮抗劑、鈉離子通道拮抗劑 '轉錄因子NF - /c B抑制劑、脂質過氧化酶抑制劑、水-乙醯化-α -連結酸性二肽酶抑制劑、胰島素樣生長因子-I、血小板來源生長因子、血小板來源生長因子類似物、上皮增殖因子、神經生長因子、肉驗衍生物、尿核苷' 5 -羥基-1 -曱基乙内醯脲、E G Β - 7 61、必莫克默、舒得塞、Υ - 1 2 8、止瀉劑、瀉劑、血管升壓素轉移酶抑制劑、 ⑧ 312ΧΡ/發明說明書(補件)/94-07/94106583 1351400D _Hand inositol 'glycogen synthase kinase-3 inhibitor, glycosidic peptide-1, glycophorin-like peptide-1 analog, glycophorin-like peptide-1 agonist, fragrant tree, It is better to use at least one agent selected from the group consisting of fragrant tree auxin and auxin agonist; and is provided by a skin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, and an insulin secretion promoter. It is preferable to use at least one of the group consisting of SGLT2 activity inhibitor and insulin or insulin analog. Similarly for the treatment of diabetic complications, insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion promoters, SGLT2 activity inhibitors, insulin or insulin analogues, glycosaminoglycan receptor antagonists, insulin Receptor kinase stimulating agent, tripeptidase II inhibitor, dipeptidase IV inhibitor, protein tyrosine phosphatase 1 B inhibitor, glycogen phosphorylase inhibitor, glucosinolate-6-phosphatase inhibitor, fructose Diphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic glucose stimulating inhibitor, D-hand inositol, glycogen synthase kinase-3 inhibitor, glycosidic peptide-1, glycophorin-like peptide -1 Analogs, Glucagon-like peptide-1 agonist, fragrant tree, fragrant tree analog, auxin agonist, acid sugar reductase inhibitor, late glycation end product production inhibitor, protein kinase C inhibitor, 7-aminobutyric acid receptor antagonist, sodium channel antagonist 'transcription factor NF- /c B inhibitor, lipid peroxidase inhibitor, water-acetylated-α-linked acid dipeptide Enzyme inhibitor, insulin-like growth factor-I, Platelet-derived growth factor, platelet-derived growth factor analog, epithelial growth factor, nerve growth factor, meat test derivative, uridine nucleoside '5-hydroxy-1 -mercaptoin-9, EG Β - 7 61, must Mokmer, Shudset, Υ - 1 2 8, antidiarrheal, laxative, vasopressin transferase inhibitor, 8 312 ΧΡ / invention specification (supplement) /94-07/94106583 1351400

中性肽鐽内切酶抑制劑、血管升壓素11受體拮抗劑、内皮素轉移酶抑制劑、内皮素受體促效劑及利尿劑等所構成群組中至少選取1種藥劑組合使用較好；而由醛糖還原酶抑制劑、血管升壓素轉移酶抑制劑、中性肽鏈内切酶抑制劑及血管升壓素 I I受體拮抗劑等所構成群組中至少'選取 1 種藥劑組合使用更好。又，於治療肥胖症方面，由胰島素敏感性增強劑 '糖吸收抑制劑、雙胍藥、胰島素分泌促進劑、SGLT2活性抑制劑、胰島素或胰島素類似物、升糖素受體拮抗劑、胰島素受體激酶刺激劑、三肽酶I I抑制劑、二肽酶I V抑制劑、蛋白質酪胺酸磷酸酶1 B抑制劑、肝醣磷酸化酶抑制劑、葡萄糖-6 -磷酸酶抑制劑、果糖二磷酸酶抑制劑、丙酮酸去氫酶抑制劑、肝醣新生抑制劑、D -手肌醇、肝醣合成酵素激酶-3抑制劑、升糖素樣胜肽-1、血糖素樣胜肽-1類似物、血糖素樣胜肽-1促效劑、香樹素、香樹素類似物、香樹素促效劑'/? 3 -腎上腺素受體促效劑及食慾抑制劑等所構成群組中至少選取1種藥劑組合使用較好；而由糖吸收抑制劑、S G L T 2活性抑制劑、泠3 -腎上腺素受體促效劑及食慾抑制劑等所構成群組中至少選取1種藥劑組合使用更好。使用本發明之醫藥組成物於實際治療時，可因應用法而使用各種劑型。此種劑型可為粉劑、顆粒劑、細粒劑、乾糖漿劑、鍵劑、膠囊劑、注射劑、液劑、軟膏劑、栓塞劑、貼付劑等，以經口或非經口方式投藥。又本發明之醫藥組成物亦包括包含有消化道黏膜附著性製劑等緩釋性製劑 77 312XP/發明說明書(補件)/94-07/941065S3 1351400 (例如，國際公開公報第W 0 9 9 / 1 0 0 1 0號、國際公開公報第 W 0 9 9 / 2 6 6 0 6號、日本專利特開2 0 0 1 - 2 5 6 7號公報）。此等醫藥組成物，因應其劑型，可以調劑學上使用之方法而與適當之賦形劑、分解劑、粘合劑、潤滑劑、稀釋劑、缓衝劑、等滲透壓劑 '防腐劑、濕潤劑、乳化劑、分散劑、穩定劑 '助溶劑等醫藥品添加物適當混合或稀釋•溶解，依常法進行調劑而予以製造。又，與其他藥劑組合使用時，各活性成分可同時或各別以上述相同方法製劑化而予以製At least one agent selected from the group consisting of a neutral peptide endonuclease inhibitor, a vasopressin 11 receptor antagonist, an endothelin transferase inhibitor, an endothelin receptor agonist, and a diuretic Preferably, at least one of the group consisting of an aldose reductase inhibitor, a vasopressin transferase inhibitor, a neutral endopeptidase inhibitor, and a vasopressin II receptor antagonist It is better to use a combination of drugs. In addition, in the treatment of obesity, insulin sensitivity enhancer 'sugar absorption inhibitor, biguanide, insulin secretion promoter, SGLT2 activity inhibitor, insulin or insulin analog, glycosidic receptor antagonist, insulin receptor Kinase Stimulator, Tripeptidase II Inhibitor, Dipeptidase IV Inhibitor, Protein Tyrosine Phosphatase 1 B Inhibitor, Hepatic Glycophosphorylase Inhibitor, Glucose-6-phosphatase Inhibitor, Fructose Diphosphatase Inhibitor, pyruvate dehydrogenase inhibitor, hepatic glucose stimulating inhibitor, D-hand inositol, glycogen synthase kinase-3 inhibitor, glycosidic peptide-1, glycophorin-like peptide-1 a group consisting of a substance, a glycoprotein-like peptide-1 agonist, a fragrant tree, a fragrant tree analog, a fragrant stimulator, an adrenergic receptor agonist, and an appetite suppressant. At least one of the combinations of the agents is preferably used; and at least one of the combinations of the sugar absorption inhibitor, the SGLT 2 activity inhibitor, the 泠3-adrenergic receptor agonist, and the appetite suppressant is selected. Use better. When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms can be used depending on the application method. Such a dosage form may be a powder, a granule, a fine granule, a dry syrup, a key, a capsule, an injection, a liquid, an ointment, an embolic agent, a patch, etc., and is administered orally or parenterally. Further, the pharmaceutical composition of the present invention also includes a sustained-release preparation containing a digestive tract mucoadhesive preparation 77 312XP/invention specification (supplement)/94-07/941065S3 1351400 (for example, International Publication No. WO 9 9 / 1 0 0 1 0, International Gazette No. W 0 9 9 / 2 6 6 06, Japanese Patent Laid-Open No. 2 0 0 1 - 2 5 6 7). These pharmaceutical compositions, depending on the dosage form, may be adjusted to the appropriate methods of use, excipients, decomposers, binders, lubricants, diluents, buffers, etc., osmotic pressure agents, preservatives, A pharmaceutical additive such as a wetting agent, an emulsifier, a dispersing agent, or a stabilizer "solvent" is appropriately mixed, diluted, dissolved, and prepared by a usual method. Further, when used in combination with other agents, the active ingredients can be formulated simultaneously or separately in the same manner as described above.

造。使用本發明之醫藥組成物於實際治療時，其有效成分之上述一般式（I)表示之化合物或其藥理學上容許之鹽或該等之前驅藥之投藥量，係依患者之年齡、性別、體重、疾病及治療程度等而適當決定，但經口投藥時成人每曰約 0 . 1〜1 0 0 0 m g之範圍，非經口投藥時則成人每日約0 . 0 1〜 3 OOmg範圍，並以每日1次或分成數次適當投藥。又，與其他藥劑組合使用時，本發明之化合物之投藥量可隨其他藥劑之投藥量而減量。 (實施例）以下以實施例及試驗例進一步詳細說明本發明之内容，但本發明不受該内容之限制。 (實施例1 ) 第1步驟 1 - ( 5 -溴笨并[b ]噻吩-3 -基）-2 -苯乙酮在 0 °C下加入氣化鋁（1 · 9 g )於 5 -溴苯并噻吩（1 . 0 g ) 312XP/發明說明書(補件)/94-07/94106583 ⑧ 1351400 及笨醋酸氣（l.lg)之氣化曱烷（50mL)溶液中，在相同溫度下攪拌 2 小時。將反應混合物注入冰冷之鹽酸水溶液 (2mol/L)中後，用二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯 =8 / 1 )精製。餾除溶劑後，將殘渣之固體以己烷洗淨，得到標題化合物（1 · 1 g )。丨Η - NMR (CDCla) (5 ppm ：Made. When the pharmaceutical composition of the present invention is used in actual treatment, the compound represented by the above general formula (I) or its pharmacologically acceptable salt or the amount of the prodrug is administered according to the age and sex of the patient. The body weight, the disease, the degree of treatment, and the like are appropriately determined, but in the case of oral administration, the adult is in the range of about 0.1 to 1 0 0 mg per day, and the non-oral administration is about 0. 0 1 to 3 OOmg per day. Scope, and appropriate administration once a day or divided into several times. Further, when used in combination with other agents, the administration amount of the compound of the present invention can be reduced depending on the administration amount of the other agent. (Examples) Hereinafter, the contents of the present invention will be described in further detail by way of examples and test examples, but the invention is not limited thereto. (Example 1) Step 1 - (5-bromobenz[b]thiophen-3-yl)-2-acetophenone was added at a temperature of 0 ° C to an aluminum hydride (1 · 9 g ) at 5 - bromine Benzothiophene (1.0 g) 312XP / invention specification (supplement) /94-07/94106583 8 1351400 and a solution of acetic acid gas (l.lg) in gasified decane (50mL), stirred at the same temperature 2 hours. The reaction mixture was poured into ice-cold aqueous hydrochloric acid (2 mol/L), and extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The residue was purified by a silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 8 / 1). After distilling off the solvent, the residue solid was washed with hexane to give the title compound (1·1 g).丨Η - NMR (CDCla) (5 ppm :

4.28C2H, s), 7. 2 0 - 7. 4 0 ( 5 H, m), 7.52(1H, dd, J=1.9, 8.7Hz), 7.69(1H, d, J=8.7Hz), 8.37(1H, s), 8.98(1H, d , J = 1 . 9 H z ) 第2步驟 5 -溴-3 - ( 2 -笨乙基）笨并[b ]噻吩於室溫下加入三氟醋酸（1 0 m L )於 1 - ( 5 -溴苯并[b ]噻吩-3 -基）-2 -苯乙嗣（l.lg)及三乙基碎炫•（l.Sg)之混合物中，於室溫下攪拌2小時。將反應混合物注入冰冷之飽和碳酸鉀水溶液中，用二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷）精製，得到標題化合物（〇 . 9 4 g )。丨Η - NMR (CDCla) δ ppm : 3. 00-3. 15(4Η, m), 7. 07(1Η, s), 7 · 1 5 - 7 . 3 5 ( 5 Η， m )， 7.44C1H, dd, J=2.1, 8.5Hz), 7.7K1H, d, J=8.5Hz), 7. 86 ( 1 H, d, J = 2.1Hz) 79⑧ 3 ] 2XP/發明說明書(補件)/94-07/94】06583 1351400 第3步驟 2,3,4,6-四-夕-苄基-1- [3 - (2 -苯乙基）笨并[b]噻吩_5_基]-D -葡。底嗔聚糖4.28C2H, s), 7. 2 0 - 7. 4 0 ( 5 H, m), 7.52 (1H, dd, J=1.9, 8.7Hz), 7.69(1H, d, J=8.7Hz), 8.37( 1H, s), 8.98 (1H, d, J = 1. 9 H z ) Step 2 5 -Bromo-3 - (2-phenylethyl) benzo[b]thiophene was added at room temperature to trifluoroacetic acid ( 1 0 m L ) in a mixture of 1-(5-bromobenzo[b]thiophen-3-yl)-2-phenylethylhydrazine (l.lg) and triethyl hydrazone (l.Sg), Stir at room temperature for 2 hours. The reaction mixture was poured into ice cold saturated aqueous potassium carbonate and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane) to give the title compound (j.丨Η - NMR (CDCla) δ ppm : 3. 00-3. 15(4Η, m), 7. 07(1Η, s), 7 · 1 5 - 7 . 3 5 ( 5 Η, m ), 7.44C1H , dd, J=2.1, 8.5Hz), 7.7K1H, d, J=8.5Hz), 7. 86 ( 1 H, d, J = 2.1Hz) 798 3 ] 2XP/Invention Manual (supplement)/94- 07/94]06583 1351400 3rd step 2,3,4,6-tetra-oxime-benzyl-1-[3 -(2-phenylethyl) benzo[b]thiophene-5-yl]-D- Portuguese. Endopolysaccharide

在-78°C之氬氣環境下，加入正丁基鋰（2.44mol/L正己烷溶液，1.24mL)於 5 -溴-3 - (2 -苯乙基）苯并[b]噻吩 (0.94g)之四氬呋喃（25mL)溶液中，在相同溫度下攪拌 5 分鐘。加入2,3,4,6 -四-<?-节基-D -葡萄糖酸- 1，5_ 内酯（0 . 8 0 g )之四氫。夫。南（4 m L )溶液於此反應混合物後，升溫至0 °C攪拌3 0分鐘。將此反應混合物注入飽和氣化銨水溶液中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，以無水硫酸鎂乾燥後，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己坑/醋酸乙醋=4 / 1〜3 / 1 ) 精製，得到標題化合物（1 · 1 g )。第4步驟 5 - (2,3,4,6- 四-夕-苄基 - yS-D- 葡哌喃聚糖基）-3 - (2 -苯乙基）苯并[b]噻吩在冰浴下，加入三氟化硼·二乙醚錯合物（0 . 2 3 g )於 2,3,4,6-四-节基-1- [3 - (2_笨乙基）苯并[b]°塞吩-5 -基]-D -葡萄糖（l.lg)及三乙基矽烷（0.34g)之乙腈（1 5 m L )溶液中，將反應混合物升溫至室溫並攪拌1夜。加入飽和碳酸鉀水溶液於此反應混合物中，並攪拌 30分鐘。將混合物注入水中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/ 312XP/發明說明書(補件)/94-07/94106583 80 ⑧ 1351400 醋酸乙酯 = 6/1 ) 精製。將所得固體以己坑洗淨 >於減壓下乾燥，得到標苟 ^化合物 (〇·5g) 1 〇 Ή -NMR (CDC13 丨）δ ppm 3. 00-3. 1 5(4Η, m ), 3 . 50- 3.60(1H, m ), 3. 60-3. 70( 1 Η , m ), 3. 72(1 Η, d , J = =1 0Hz ) ,3 .75- 3.90 (4H, m ), 4 . 35-4. .45(2H, m ) ,4.55 -4.60( :1H, m) ，4 .60- 4.70 (2H, m ), 4 . 85-5. .00(3H, m ) ,6.75 -6.85( ；2H, m), 7. 00- 7.40( ：24H, m ), 7 . 48(1 H, dd,Add n-butyllithium (2.44 mol/L n-hexane solution, 1.24 mL) to 5-bromo-3-(2-phenylethyl)benzo[b]thiophene (0.94) under an argon atmosphere at -78 °C. g) In a solution of tetrahydrofuran (25 mL), stir at the same temperature for 5 minutes. 2,3,4,6-tetra-<?-nodal-D-gluconic acid-1,5-lactone (0.80 g) of tetrahydrogen was added. husband. After the solution of the south (4 m L) solution was stirred at 0 ° C for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium sulfate and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by a silica gel column chromatography (eluent solvent: hexane/ethyl acetate = 4 / 1 to 3 / 1) to give the title compound (1·1 g). Step 4 - 5,(2,3,4,6-tetra-oxo-benzyl-yS-D-pipetamylan)-3 -(2-phenylethyl)benzo[b]thiophene on ice Under the bath, boron trifluoride diethyl ether complex (0.23 g) was added to 2,3,4,6-tetra-benzyl-1-[3-(2-p-ethyl)benzo[ b]°Cet-5-yl]-D-glucose (1.lg) and triethyldecane (0.34 g) in acetonitrile (15 mL), the reaction mixture was warmed to room temperature and stirred for 1 night . A saturated aqueous solution of potassium carbonate was added to the reaction mixture and stirred for 30 min. The mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / 312XP / invention specification (supplement) / 94-07/94106583 80 8 1351400 ethyl acetate = 6/1). The obtained solid was washed with a pit and dried under reduced pressure to give the title compound (〇·5g). 1 〇Ή-NMR (CDC13 丨) δ ppm 3. 00-3. 1 5 (4 Η, m ) , 3 . 50- 3.60(1H, m ), 3. 60-3. 70( 1 Η , m ), 3. 72(1 Η, d , J = =1 0Hz ) , 3.75- 3.90 (4H, m ), 4 . 35-4. .45(2H, m ) , 4.55 -4.60( :1H, m) , 4.60- 4.70 (2H, m ), 4. 85-5. .00(3H, m ), 6.75 - 6.85 ( ; 2H, m), 7. 00- 7.40 ( :24H, m ), 7. 48 (1 H, dd,

J = 1.5, 8. 4Hz ), 7. 78(1H, d, J = 1.5Hz), 7. 86( 1 H, d, JJ = 1.5, 8. 4Hz ), 7. 78(1H, d, J = 1.5Hz), 7. 86( 1 H, d, J

=8 . 4 H z ) 第5步驟 1 - [ 3 - ( 2 - 笨乙基）苯并[b]°塞吩-5_ 基]-1_去氧-冷-D -葡哌喃聚糖在室溫下，加入三氟化硼·二乙醚錯合物（0_28g)於 5 - (2,3,4,6- 四 -0 - 苄基-冷-D- 葡哌喃聚糖基）-3 - ( 2 -苯乙基）苯并[b ]噻吩（0 . 1 g)及乙硫醇（0 · 1 6 g) 之氣化曱烷（6 m L)混合物中，於室溫下攪拌3小時。加入飽和碳酸鉀水溶液於反應混合物，以醋酸乙酯萃取。將有機層飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：氣化曱烷/曱醇=1 0 / 1〜5 / 1 )精製，得到標題化合物（〇 . 〇 3 4 g )。 Ή - NMR (CDaOD) 6 ppm: 3. 00-3. 1 0(2H, m), 3. 10-3. 20(2H, m), 3. 4 0 - 3. 6 0 ( 4H, m), 3. 74( 1 H, dd, J = 5. 3, 11. 8Hz), 3 . 9 1 ( 1 H, dd, J = 1. 7, 11 . 8Hz ), 4. 2 9 ( 1 H, d, J = 9.2Hz), 7. 10-7. 30 ( 6H, m ), 81 312XP/發明說明書(補件)/SM-07/94106583 1351400 7. 4 0 - 7. 5 0 ( 1 H, m) , 7 · 8 0 - 7 · 9 0 ( 2 Η，m ) (實施例2 ) 第1步驟 1-(2,4 -二甲氧笨基）-2, 3, 4,6 -四-苄基-D-葡哌喃聚糖在-78°C氬氣環境下，加入正丁基鋰（2.44mol/L正己烷溶液，3.1mL)於 2,4 -溴苯（1.6g)之四氫呋喃（40mL)溶液中，在相同溫度下搜拌5分鐘。加入2,3,4,6 -四-(7-苄=8 . 4 H z ) Step 5 - [ 3 - ( 2 - Phenethyl) benzo[b]°Cet-5-yl]-1_deoxy-cold-D-glucopyran Add boron trifluoride diethyl ether complex (0-28 g) to 5-(2,3,4,6-tetra-O-benzyl-cold-D-glucopyranosyl)-3 at room temperature - ( 2 -Phenylethyl)benzo[b]thiophene (0.1 g) and ethanethiol (0 · 16 g) in a mixture of vaporized decane (6 m L), stirred at room temperature 3 hour. A saturated aqueous solution of potassium carbonate was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was purified by a silica gel column chromatography (eluent solvent: hexanes / hexanes / / / / / / / / / / / / / / / / / / Ή - NMR (CDaOD) 6 ppm: 3. 00-3. 1 0(2H, m), 3. 10-3. 20(2H, m), 3. 4 0 - 3. 6 0 ( 4H, m) , 3. 74( 1 H, dd, J = 5. 3, 11. 8Hz), 3. 9 1 ( 1 H, dd, J = 1. 7, 11 . 8Hz ), 4. 2 9 ( 1 H, d, J = 9.2Hz), 7. 10-7. 30 ( 6H, m ), 81 312XP / invention manual (supplement) / SM-07/94106583 1351400 7. 4 0 - 7. 5 0 ( 1 H, m) , 7 · 8 0 - 7 · 9 0 ( 2 Η, m ) (Example 2) Step 1 1-(2,4-dimethoxyphenyl)-2, 3, 4,6 -tetra- Benzyl-D-glucopyranoside was added to n-butyllithium (2.44 mol/L n-hexane solution, 3.1 mL) in 2,4-bromobenzene (1.6 g) in tetrahydrofuran under an argon atmosphere at -78 °C. In a (40 mL) solution, mix at the same temperature for 5 minutes. Add 2,3,4,6-tetra-(7-benzyl

基-D -葡萄糖酸-1，5 -内酯（2.0g)之四氫呋喃（6mL)溶液於反應混合物，將反應混合物升溫至0 °C並攪拌1小時。將反應混合物注入飽和氣化銨水溶液中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烧/醋酸乙S旨=4/1〜3/1〜2/1〜1/1)精製，得到標題化合物（1 · 7 g) » 第2步驟 1-去氧-2, 3, 4, 6 -四--苄基-1-(2, 4 -二曱氧苯基）-/9 - D -葡°底喃聚糖在冰浴下，加入三氟化硼·二乙醚錯合物（〇 · 4 0 g )於 1- (2,4 -二曱氧苯基）-2,3,4,6 -四-ί?-苄基-D-葡哌喃聚糖（1.7g)及三乙基矽烷（〇.59g)之乙腈（20mL)溶液中，升溫至室溫並攪拌1夜。加入飽和碳酸鉀水溶液於反應混合物中，攪拌3 0分鐘。將混合物注入水中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂 312XP/發明說明書(補件)/94-07/94106583 82 ⑧ 1351400 乾燥後，於減壓下餾除溶劑。殘渣以矽膠管柱色層分析法 (洗提溶劑：正己烷/醋酸乙酯=6 / 1 )精製，得到標題化合物（1 . 1 g )。 Ή - NMR (CDCls) δ ppm : 3. 5 5 - 3. 6 5 ( 1 H, m), 3 . 6 2 - 3 . 7 1 ( 1 Η , m), 3. 71-3. 90(4Η, m), 3. 75(3Η, s ), 3. 82(3Η, s), 3. 95(1 Η, d, J = 1 0. 7Ηζ), 4.43(1Η, d, J= 10.4Hz), 4.53(1Η, d, J= 12.1Hz),A solution of the base-D-gluconic acid-1,5-lactone (2.0 g) in tetrahydrofuran (6 mL) was added to the reaction mixture, and the mixture was warmed to 0 ° C and stirred for 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium sulfate and extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The residue was purified by a silica gel column chromatography (eluent solvent: hexanes / ethyl acetate / / / / / / / / / / / / / / / / / / / » Step 2 1-Deoxy-2,3,4,6-tetra-benzyl-1-(2,4-dioxaphenyl)-/9-D-glucopyran in ice Under the bath, add boron trifluoride diethyl ether complex (〇·40g) to 1-(2,4-dioxaphenyl)-2,3,4,6-tetra--?-benzyl A solution of basal-D-glucopyran (1.7 g) and triethyl decane (〇.59 g) in acetonitrile (20 mL) was warmed to room temperature and stirred overnight. Saturated aqueous potassium carbonate solution was added to the reaction mixture and stirred for 30 minutes. The mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate 312 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 6 / 1) to give the title compound (1.1 g). Ή - NMR (CDCls) δ ppm : 3. 5 5 - 3. 6 5 ( 1 H, m), 3 . 6 2 - 3 . 7 1 ( 1 Η , m), 3. 71-3. 90 (4Η , m), 3. 75(3Η, s ), 3. 82(3Η, s), 3. 95(1 Η, d, J = 1 0. 7Ηζ), 4.43(1Η, d, J= 10.4Hz) , 4.53 (1Η, d, J= 12.1Hz),

4. 6 0 - 4. 8 0 ( 3 H, m ) , 4 . 8 5 - 4. 9 2 ( 2H, m ) , 4.95(1H, d, J4. 6 0 - 4. 8 0 ( 3 H, m ) , 4 . 8 5 - 4. 9 2 ( 2H, m ) , 4.95 (1H, d, J

=1 1 . 0Hz), 6.46C1H, d, J=2.6Hz), 6.53C1H, dd, J = 2.6, 8.5Hz), 6. 9 0 - 6. 9 5 ( 1 H, m), 7. 1 0 - 7. 4 0 ( 2 0 H, m) 第3步驟 1-去氧-1- (2, 4 -二曱氧苯基）-冷-D -葡哌喃聚糖加入 1 0 %鈀碳粉末（0 · 5 0 g )於 1 -去氧-2，3，4，6 -四-夕-苄基-1-(2,4 -二曱氧苯基）-召-D-葡哌喃聚糖（l.lg)之甲醇（10mL)與四氫°夫喃（5mL)溶液中，在氫氣環境下室溫攪拌5小時。濾除不溶物，於減壓下餾除濾液之溶劑，得到標題化合物（0 . 4 7 g )。 Ή - NMR (CDaOD) δ ppm : 3. 3 0 - 3. 4 2 ( 2 Η, m) , 3. 4 4 - 3. 5 0 ( 1 Η, m), 3. 5 0 - 3. 6 0 ( 1 Η, m ), 3. 65(1 Η, dd, J = 5.6, 11. 9Ηζ ), 3. 78(3Η, s), 3. 8 0(3Η, s), 3.84(1Η, dd, J=2.0, 11.9Hz), 4.60C1H, d, J = 9.7Hz), 6. 5 0 - 6. 5 5 ( 2 H, m ), 7. 2 5 - 7. 3 5 ( 1 Η , m ) 第4步驟 (2, 4 -二 83⑧ 1-去氧-2,3,4,6 -四-夕-三甲基乙醯基 312XP/發明說明書(補件)/94-07/94106583 1351400 曱氧苯基）-点-D-葡哌喃聚糖=1 1 . 0Hz), 6.46C1H, d, J=2.6Hz), 6.53C1H, dd, J = 2.6, 8.5Hz), 6. 9 0 - 6. 9 5 ( 1 H, m), 7. 1 0 - 7. 4 0 ( 2 0 H, m) Step 3 1-Deoxy-1-(2,4-dioxaphenyl)-cold-D-glucosamine added 10% palladium on carbon Powder (0 · 50 g) in 1-deoxy-2,3,4,6-tetra-oxime-benzyl-1-(2,4-dioxaphenyl)-call-D-glucosin A solution of xylan (1. lg) in methanol (10 mL) and tetrahydrofuran (5 mL) was stirred at room temperature under hydrogen atmosphere for 5 hr. The insoluble material was filtered out, and the solvent was evaporated to dryness crystall Ή - NMR (CDaOD) δ ppm : 3. 3 0 - 3. 4 2 ( 2 Η, m) , 3. 4 4 - 3. 5 0 ( 1 Η, m), 3. 5 0 - 3. 6 0 ( 1 Η, m ), 3. 65(1 Η, dd, J = 5.6, 11. 9Ηζ ), 3. 78(3Η, s), 3. 8 0(3Η, s), 3.84(1Η, dd, J=2.0, 11.9Hz), 4.60C1H, d, J = 9.7Hz), 6. 5 0 - 6. 5 5 ( 2 H, m ), 7. 2 5 - 7. 3 5 ( 1 Η , m ) Step 4 (2, 4 - 2 838 1-deoxy-2,3,4,6-tetra-oxime-trimethylacetamido 312XP/invention specification (supplement)/94-07/94106583 1351400 Phenyl)-dot-D-glucopyran

在室溫下加入三曱基乙醯氯U.lg)於 1- 去氧-1- (2,4 -二曱氧笨基）-冷-D -葡哌喃聚糖（〇_47g) 之。比啶（I 0 m L )溶液中，於室溫下欖拌1夜。將反應混合物注入水中，以二乙醚萃取。將有機層用水、1 m ο 1 / L鹽酸水溶液及飽和食鹽水洗淨，並以無水硫酸鎂乾燥。於減壓下餾除溶劑，將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯=3 / 1〜1 / 1 )精製。將所得化合物（〇 · 5 1 g ) 溶解於0比咬（6mL)，加入三曱基乙酿氣（〇_23g)及 4 -(介，少-二甲胺基）吡啶（0 . 0 7 9 g )，於5 0 °C攪拌1夜。於反應混合物中再加入三曱基乙醯氣（0 . 1 2 m L )，於8 0 °C攪拌 1 夜。將反應混合物注入水中，以二乙醚萃取。將有機層用水、1 m ο 1 / L鹽酸水溶液及飽和食鹽水洗淨，並以無水硫酸鎂乾燥，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯=4 / 1〜2 / 1 )精製，得到標題化合物（0 · 5 8 g )。 1Η - NMR (CDCIO <5 ppm ： 0. 86(9H, s), 1 . 1 2(9H, s), 1 · 1 6 ( 9 H，s )，1 · 2 2 ( 9 H，s )， 3.77C3H, s), 3. 78(3 H, s), 3.80-3.90ΠΗ, m), 4.09(1H, dd, J = 4. 2, 12.4Hz)，4. 19(1H, dd, J= 1. 9, 12. 4Hz),Addition of trimethylsulfonium chloride U.lg) to 1-deoxy-1-(2,4-dioxaphenyl)-cold-D-glucopyran (〇_47g) at room temperature . In a solution of pyridine (I 0 m L ), it was stirred at room temperature for 1 night. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water, a 1 m aqueous solution of hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3 / 1 to 1 / 1). The obtained compound (〇·5 1 g ) was dissolved in 0 to bite (6 mL), and triterpene ethylbenzene gas (〇_23 g) and 4-(di-dimethylamino)pyridine (0. 0 7) were added. 9 g ), stirred at 50 ° C for 1 night. Further, tridecyl ethane oxime (0.12 m L) was added to the reaction mixture, and the mixture was stirred at 80 ° C for 1 night. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water, a 1 m aqueous solution of hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 1Η - NMR (CDCIO <5 ppm : 0. 86(9H, s), 1. 1 2(9H, s), 1 · 1 6 ( 9 H, s ), 1 · 2 2 ( 9 H, s ) , 3.77C3H, s), 3. 78(3 H, s), 3.80-3.90ΠΗ, m), 4.09(1H, dd, J = 4. 2, 12.4Hz), 4. 19(1H, dd, J = 1. 9, 12. 4Hz),

4. 8 5 - 5. 0 0 ( 1 H, m), 5. 2 5 - 5. 5 0 ( 3 H , m), 6.37(1H, d, J = 2.6Hz), 6.47(1H, dd, J=2.6, 8.5Hz), 7 . 1 0 - 7 . 3 0 ( 1 H, m ) 第5步驟 84 312XP/發明說明書(補件)/94-07/94 ] 06583 1351400 2 -苯基-2’ -羥基-4’ -甲氧基-5’ - (2,3,4,6- 四--三甲基乙酿-yS -D_葡派01¾聚糖基）苯丙明在冰浴下，加入氣化lS(1.5g)於 1_去氧_ 2，3，4，6-四-夕-三曱基乙醒-I - (2,4 -二甲氧苯基）-冷-D -葡略喃聚糖（0.58g)之二乙fii(9mL)溶液中，搜拌5分鐘。在室溫下，於混合物中加入3 -苯基丙酸氯（0 · 4 6 g )，將反應液升溫至室溫攪拌4日。將反應混合物注入冰冷之2 m ο 1 / L 鹽酸水溶液中，以二乙醚萃取。將有機層用水及飽和食鹽4. 8 5 - 5. 0 0 ( 1 H, m), 5. 2 5 - 5. 5 0 ( 3 H , m), 6.37 (1H, d, J = 2.6Hz), 6.47(1H, dd, J=2.6, 8.5Hz), 7. 1 0 - 7 . 3 0 ( 1 H, m ) Step 5 84 312XP / Invention Manual (supplement) /94-07/94 ] 06583 1351400 2 -Phenyl-2 '-Hydroxy-4'-methoxy-5'-(2,3,4,6-tetra-trimethylethene-yS-D_加派013⁄4 glycan) phenylpropanol in an ice bath , adding gasification lS (1.5g) to 1_deoxy-2,3,4,6-tetra-oxime-trimethyl ketone-I-(2,4-dimethoxyphenyl)-cold-D - A solution of glucomannan (0.58 g) in diethylene fii (9 mL) was mixed for 5 minutes. To the mixture was added 3 -phenylpropionic acid chloride (0 · 4 6 g) at room temperature, and the mixture was warmed to room temperature and stirred for 4 days. The reaction mixture was poured into ice cold 2 m EtOAc / EtOAc. Organic layer with water and saturated salt

水洗淨，並以無水硫酸鎂乾燥，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯 =6 / 1〜3 / 1 )精製，得到標題化合物（0 · 3 5 g )。 Ή - NMR (CDCla) <5 ppm : 0. 87(9H, s), 1. 1 2(9H, s), 1. 14(9H, s), 1. 16(9H, s), 3. 00-3. 10(2H, m), 3. 15-3. 40(2H, m), 3. 8-3. 9(4H, m), 4. 05 ( 1 H, dd, J = 4. 4, 12.4Hz), 4 . 1 8 ( 1 H, dd, J = 1.9, 12.4Hz), 4. 8 0 - 5 . 0 0 ( 1 H, m ), 5. 2 0 - 5. 5 0 ( 3 H, tn), 6. 37( 1 H s), 7. 20-7.35(5H, m), 7.73(1H, s), 12.82(1H, s) 第6步驟甲氧 )-葡 2- 笨基 -2’ -(甲氧羰基曱羥基）-4 ’ 基-5， - (2,3,4,6 -四-夕-三曱基乙醯基-石哌喃聚糖基）苯丙酮在室溫下加入碳酸鉀（0 . 〇 9 6 g )與 2 -溴醋酸甲酯 (0.085g)於 2- 苯基 _2’ - 羥基 -4’ - 甲氧葡基-5’ - (2,3,4,6 -四-汐-三甲基乙醞基-万 3 ] 2XP/發明說明書(補件)/94-07/94106583 85 ⑧ 1351400 哌喃聚糖基）笨丙鲷（0.35g)之 Ν,Ν -二曱基曱醯胺（6mL) 溶液中，於室溫下攪拌8小時。將反應混合物注入0 · 5 m ο 1 / L 鹽酸水溶液中，以二乙醚萃取。將有機層用水（2次）及飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑，得到標題化合物（0 · 3 8 g )。 Ή - NMR (CDC13) δ ppm : 0. 85(9H, s), 1.12(9H, s)， 1.17(9H, s), 1. 22(9H, s), 2. 9 5 - 3. 0 5 ( 2 H, m ), 3. 3 0 - 3. 4 0 ( 2 H, m), 3. 70(3H, s), 3. 7 5 - 3. 8 5 ( 1 H, m), 3. 86(3H, s), 4. 08(1H, dd, J = 4 . 1 , 12.4Hz), 4. 20(1H, dd, J = 1.7, 12. 4Hz), 4. 6 0 - 4. 8 0 ( 3 H, m), 5. 2 0 - 5. 6 0 ( 3 H, m), 6.25(1H, s), 7 . 15 - 7. 35(5H, m), 7. 85(1H, s) 第7步驟 2- 苯基 -2’ -(羧基曱基氧化）-4 ’ - 甲氧基-5’ - (2,3,4,6 -四-夕-三甲基乙醯基-/S - D-葡The organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 6 / 1 to 3 / 1) to give the title compound (0·3 5 g). Ή - NMR (CDCla) <5 ppm : 0. 87(9H, s), 1. 1 2(9H, s), 1. 14(9H, s), 1. 16(9H, s), 3. 00-3. 10(2H, m), 3. 15-3. 40(2H, m), 3. 8-3. 9(4H, m), 4. 05 ( 1 H, dd, J = 4. 4, 12.4 Hz), 4 . 1 8 ( 1 H, dd, J = 1.9, 12.4 Hz), 4. 8 0 - 5 . 0 0 ( 1 H, m ), 5. 2 0 - 5. 5 0 ( 3 H, tn), 6. 37( 1 H s), 7. 20-7.35(5H, m), 7.73(1H, s), 12.82(1H, s) Step 6: Oxygen) - Portuguese 2 - Stupid Benzyl-2'-(methoxycarbonylhydrazino)-4'yl-5,-(2,3,4,6-tetra-s-tris-trimethylethenyl-piperazinyl)propiophenone Potassium carbonate (0. 〇9 6 g) and methyl 2-bromoacetate (0.085 g) were added at room temperature to 2-phenyl-2'-hydroxy-4'-methoxy-glucosyl-5'- (2, 3,4,6-tetra-indole-trimethylethenyl-10,0003] 2XP/Invention Manual (supplement)/94-07/94106583 85 8 1351400 Piperona-based) Stupid (0.35g) Thereafter, it was stirred at room temperature for 8 hours in a solution of hydrazine-dihydrazinamide (6 mL). The reaction mixture was poured into 0. 5 m ο 1 / L aqueous hydrochloric acid and extracted with diethyl ether. The organic layer was washed with water (2×) and brine and dried over anhydrous magnesium sulfate. Ή - NMR (CDC13) δ ppm : 0. 85(9H, s), 1.12(9H, s), 1.17(9H, s), 1. 22(9H, s), 2. 9 5 - 3. 0 5 ( 2 H, m ), 3. 3 0 - 3. 4 0 ( 2 H, m), 3. 70(3H, s), 3. 7 5 - 3. 8 5 ( 1 H, m), 3. 86(3H, s), 4. 08(1H, dd, J = 4. 1 , 12.4Hz), 4. 20(1H, dd, J = 1.7, 12. 4Hz), 4. 6 0 - 4. 8 0 ( 3 H, m), 5. 2 0 - 5. 6 0 ( 3 H, m), 6.25(1H, s), 7. 15 - 7. 35(5H, m), 7. 85(1H, s) Step 7 2-Phenyl-2'-(carboxyindenyloxy)-4'-methoxy-5'-(2,3,4,6-tetra-oxime-trimethylethenyl- /S - D-Port

哌喃聚糖基）笨丙酮在室溫下加入 2mol/L氫氧化鈉水溶液（0.18mL)於 2-苯基 -2’ -(曱氧羰基甲基氧化）_4’ -甲氧基-5’ - (2, 3, 4, 6 -四-三曱基乙醯基-/3 - D-葡略喃聚糖基）笨丙_(0.15g)之四氫0夫喃（5mL)溶液中，於室溫下攪拌1夜。於反應混合物中加入2 m ο 1 / L氫氧化鈉水溶液（0 · 3 6 m L )，於室溫下攪拌5小時。於反應混合物中再加入5 m ο 1 / L氫氧化鈉水溶液（0 · 0 7 3 m L )，於室溫下攪拌5小時。加入 1 m ο 1 / L 鹽酸水溶液於反應混合物，使之成為酸 86 3]2XP/發明說明書(補件)/94-07/94!〇6583 1351400 性，再用二乙醚萃取。將有機層用飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑，得到標題化合物 (0.15g)。 Ή - NMR (CDCla) δ ppm: 0.87(9H, s), 1.12(9H, s), 1.15(9H, s), 1.17(9H, s), 3.00-3. 10(2H, m), 3 . 2 0 - 3. 4 0 ( 2 H, m), 3. 80-3. 95 (4H, m)， 3.89(3H, m), 4.05C1H, dd, J=4.4, 12.5Hz), 4.18(1H, dd, J=1.9, 12.5Hz), 4.74(2H, s), 4 . 8 0 - 5 . 0 0 ( 1 H , m ),Addition of 2 mol/L aqueous sodium hydroxide solution (0.18 mL) to 2-phenyl-2'-(indolylcarbonylcarbonylmethyl)_4'-methoxy-5' at room temperature - (2, 3, 4, 6 -tetra-trimethylethenyl-/3 - D-gluconosyl), a solution of phenylpropanol (0.15 g) in tetrahydrooxan (5 mL), Stir at room temperature for 1 night. 2 m ο 1 / L sodium hydroxide aqueous solution (0 · 3 6 m L ) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. Further, 5 m ο 1 / L sodium hydroxide aqueous solution (0 · 0 7 3 m L ) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. A 1 m ο 1 / L aqueous solution of hydrochloric acid was added to the reaction mixture to make an acid 86 3] 2 XP / invention specification (supplement) / 94-07/94 〇 6583 1351400, and extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Ή - NMR (CDCla) δ ppm: 0.87 (9H, s), 1.12 (9H, s), 1.15 (9H, s), 1.17 (9H, s), 3.00-3. 10(2H, m), 3 . 2 0 - 3. 4 0 ( 2 H, m), 3. 80-3. 95 (4H, m), 3.89 (3H, m), 4.05C1H, dd, J=4.4, 12.5Hz), 4.18(1H , dd, J=1.9, 12.5Hz), 4.74(2H, s), 4. 8 0 - 5 . 0 0 ( 1 H , m ),

5. 2 0 - 5. 5 0 ( 3 H, m ) , 6. 38(1H, s), 7. 15-7. 35(5H, m), 7. 80(1H, s ) 第8步驟 1 - [6 -甲氧基- 3- (2 -苯乙基）苯并[b]呋喃- 5-基]-1- 去氧 - 2,3,4,6- 四 - 0 - 三甲基乙醯基-/9 - D -葡略喃聚糖加入醋酸酐（0.40g)於 2 -苯基-2’ _(錄基甲基氧化）-4’ -甲氧基-5’ - (2,3,4,6 -四-0-三甲基乙醯基-冷-D -葡哌喃聚糖基）苯丙酮（0 · 1 5 g )、醋酸（4 · 3 g ) 及醋酸鈉（0 . 3 7 g )之混合物中，於1 1 5 °C下加熱回流1夜。將反應混合物冷卻至室溫後注入水中，用二乙醚萃取。將有機.層用水（2次）、碳酸氫鈉水溶液、水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥後，於減壓下餾除溶劑。將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯=8 / 1 ) 精製，得到標題化合物（0 . 0 3 g )。 Η - NMR (CDC13) 5 ppm : 312XP/發明說明書(補件)/9107/94106583 87 ⑧ 1351400 0. 81(9H, s ), 1 . 13(9H, s), 1.18(9H, s), 1. 21(9H, s ) 2. 85-3. 05(4H, m), 3. 85(3H, s), 3. 85-3. 95(1H, m ) .4. 1 0( 1 Η, d d , J =4.6, 12.6Hz), 4 .23( 1 H, dd, J = 1.8 12.6Hz), 5.00 -5. 25( 1 H, m), 5. 3 0 - 5. 4 0 ( 1 H, m ) 5. 4 0 - 5. 6 0 ( 2H, m), 6. 93(1H, s), 7. 10-7. 75(4H, m ) 7. 2 5 - 7. 3 5 ( 2 H, m ) , 7. 53( 1 H, s ) 第9步驟 1 - [ 6 -曱氧基- 3- (2-苯乙基）苯并[b]呋喃- 5-5. 2 0 - 5. 5 0 ( 3 H, m ) , 6. 38(1H, s), 7. 15-7. 35(5H, m), 7. 80(1H, s ) Step 8 - [6-methoxy-3-(2-phenylethyl)benzo[b]furan-5-yl]-1-deoxy-2,3,4,6-tetra- 0-trimethyl Mercapto-/9-D-glucomannan was added to acetic anhydride (0.40 g) to 2-phenyl-2'-(N-methyl-oxidized)-4'-methoxy-5'- (2, 3,4,6-tetra-O-trimethylethenyl-cold-D-glucopyranosyl)propiophenone (0 · 15 g), acetic acid (4 · 3 g ) and sodium acetate (0 In a mixture of 3 7 g ), it was heated to reflux at 1 15 ° C for 1 night. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether. The organic layer was washed with water (2 times), aqueous sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 8 / 1) to give the title compound (0.33 g). Η - NMR (CDC13) 5 ppm : 312XP / invention specification (supplement) / 9107/94106583 87 8 1351400 0. 81(9H, s ), 1. 13(9H, s), 1.18(9H, s), 1 21(9H, s ) 2. 85-3. 05(4H, m), 3. 85(3H, s), 3. 85-3. 95(1H, m ) .4. 1 0( 1 Η, Dd , J = 4.6, 12.6 Hz), 4 .23 ( 1 H, dd, J = 1.8 12.6 Hz), 5.00 -5. 25( 1 H, m), 5. 3 0 - 5. 4 0 ( 1 H , m ) 5. 4 0 - 5. 6 0 ( 2H, m), 6. 93(1H, s), 7. 10-7. 75(4H, m ) 7. 2 5 - 7. 3 5 ( 2 H, m ) , 7. 53( 1 H, s ) Step 9 - [ 6 -decyloxy-3-(2-phenylethyl)benzo[b]furan- 5-

基]-1-去氧-冷-D -葡略。南聚糖加入曱醇鈉（28%甲醇溶液，0.038mL)於 1- [6 -甲氧基- 3- (2-笨乙基）苯并[b]。夫喊基]_1_去氧--2,3,4,6 -四-三曱基乙醯基-/3 - D-葡哌喃聚糖（0 . 0 3 g )之甲醇（4 m L )懸浮液中，在5 0 °C下攪拌6小時。將反應混合物直接以矽膠管柱色層分析法（洗提溶劑：氣化曱烷/曱醇=1 0 / 1〜5 / 1 ) 精製，得到標題化合物 • ( 0 _ 0 1 5 g )。 Ή - NMR (CD3〇D) 5 ppm : 2. 9 0 - 3. 0 5 ( 4 H, m), 3 . 3 0 - 3. 5 5 ( 3 Η , m), 3 . 5 5 - 3. 6 5 ( 1 Η, m), 3 . 7 0(1 Η, dd, J = 5.6， 12. ΟΗζ ), 3 . 8 0 - 3. 9 5 ( 1 Η， m ), 4. 7 0 - 4. 9 0 ( 1 Η, m ), 7. 07 ( 1 Η, s ), 7. 10-7. 30(5Η, m ), 7. 32(1Η, s), 7. 57(1Η, s) (實施例3 ) 1 - [ 3 - ( 2 -笨乙基）苯并[b]°塞吩-5-基]-1-去氧-6 - Θ -乙氧羰基-y? - D -葡哌喃聚糖 3 i 2χρ/發明說明書(補件)/94-0刀94106583 88Base]-1-deoxy-cold-D-Portuguese. Nannan Sodium decoxide (28% methanol solution, 0.038 mL) was added to 1-[6-methoxy-3-(2-ethylidene)benzo[b].喊基 base]_1_deoxy--2,3,4,6-tetra-trimethylethenyl-/3-D-glucopyran (0. 0 3 g) of methanol (4 m L The suspension was stirred at 50 ° C for 6 hours. The reaction mixture was purified directly by EtOAc EtOAc (EtOAc: EtOAc (EtOAc) Ή - NMR (CD3〇D) 5 ppm : 2. 9 0 - 3. 0 5 ( 4 H, m), 3 . 3 0 - 3. 5 5 ( 3 Η , m), 3 . 5 5 - 3. 6 5 ( 1 Η, m), 3 . 7 0 (1 Η, dd, J = 5.6, 12. ΟΗζ ), 3 . 8 0 - 3. 9 5 ( 1 Η, m ), 4. 7 0 - 4 . 9 0 ( 1 Η, m ), 7. 07 ( 1 Η, s ), 7. 10-7. 30(5Η, m ), 7. 32(1Η, s), 7. 57(1Η, s) (Example 3) 1 - [ 3 - ( 2 -ethylidene)benzo[b]°cephen-5-yl]-1-deoxy-6 -indole-ethoxycarbonyl-y?-D-gluco Piperubicin 3 i 2χρ/Invention Manual (supplement)/94-0 knife 94106583 88

1351400 在0°C下加入氣蟻酸乙酯（l.lmL)於1- [3 - (2 -苯乙基）苯并[b]°塞吩-5-基]_1_去氧-jS - D-葡略0^聚糖 (0.19g)之 2,4,6 -三甲基吡啶（2mL)溶液中，於室溫下攪拌7小時。將反應混合物注入1 0 %檸檬酸水溶液中，用醋酸乙萃取。將有機層用飽和食鹽水洗淨，並以無水硫酸鎂乾燥。餾除溶劑後，將殘渣以矽膠管柱色層分析法（洗提溶劑：氣化曱烷/甲醇=2 0 / 1 ) 精製，得到標題化合物 (0 . 1 6 g )。1351400 Adds ethyl antsulfate (1.lmL) at 1-[3 - (2-phenylethyl)benzo[b]°cephen-5-yl]_1_deoxy-jS-D at 0 °C A solution of glucosinolate (0.19 g) in 2,4,6-trimethylpyridine (2 mL) was stirred at room temperature for 7 hr. The reaction mixture was poured into a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by EtOAc EtOAcjjjjjjj

Ή - NMR (CDsOD) ό ppm ： 1 . 20(3H, t, J = 7.0Hz), 2. 95-3. 1 0(2H, m ), 3. 10-3. 20(2H, m), 3. 3 5 - 3. 4 5 ( 1 H, m), 3. 4 5 - 3. 5 7 ( 2 H, m), 3. 6 0 - 3. 7 0 ( 1 H, in), 4.1K2H, q, J=7.0Hz), 4.29(1H, d, J = 9. 4Hz ) , 4. 34(1H, dd, J = 5.6, 11.7Hz), 4. 48(1H, dd, J = 1 . 9, 11.7Hz)，7. 10-7. 30(6H, m) , 7. 35-7. 45(1H, m), 7. 7 5 - 7. 8 5 ( 2 H, m ) ^ (實施例4〜1 4 ) 使用相對應之原料化合物，以與實施例 1相同之操作，製得表1〜2所記載之化合物。 312XP/發明說明書(補件)/94-07/94106583 89 ⑧ 1351400 表 1 ]Ή - NMR (CDsOD) ό ppm : 1 . 20 (3H, t, J = 7.0Hz), 2. 95-3. 1 0(2H, m ), 3. 10-3. 20(2H, m), 3. 3 5 - 3. 4 5 ( 1 H, m), 3. 4 5 - 3. 5 7 ( 2 H, m), 3. 6 0 - 3. 7 0 ( 1 H, in), 4.1K2H , q, J=7.0Hz), 4.29(1H, d, J = 9. 4Hz), 4. 34(1H, dd, J = 5.6, 11.7Hz), 4. 48(1H, dd, J = 1 . 9, 11.7 Hz), 7. 10-7. 30(6H, m), 7. 35-7. 45(1H, m), 7. 7 5 - 7. 8 5 ( 2 H, m ) ^ (implementation Examples 4 to 1 4) The compounds described in Tables 1 to 2 were obtained by the same procedures as in Example 1 using the corresponding starting materials. 312XP/Invention Manual (supplement)/94-07/94106583 89 8 1351400 Table 1]

實施例编號化學結搆式 'H-NMR (CD3OD) «ppm 實施例4 OH 3.35-3.55 (4H, m), 3.71 (lH, dd, J=5.4, 12.0Hz), 3.89 (1H, dd, J=1.9, 12.0Hz), 4.21 (2H, s), 4.23 (1H, d, J=9.6Hz), 7.11 (1H, s), 7.15-7.30 (5H, m), 7.43 (1H, dd, J=1.5, 8.2Hz), 7.81 (lH, d, J=1.5Hz), 7.83 (1H, d, J=8.2Hz) 賁施例5 1 Q Os 2.90-3.05 (2H, m), 3.05-3.20 (2H, m), 3.40-3.60 (4H, m), 3.70-3.80 (4H, m), 3.85-3.95 (1H, m), 4.29 (lH, d, J=9.3 Hz), 6.75-6.85 (2H, m), 7.05-7.15 (3H, m), 7.44 (lH, dd, J=1.4, 8.3Hz), 7.75-7.85 (2H, m) 實施例6 Η〇"'ίΝγ^··*ΟΗ K 3.00-3.10 (2H, m), 3.10-3.20 (2H, m), 3.40-3.55 (4H, m), 3.74 (lH, dd, J=5.3, 12.0Hz), 3.91 (1H, dd, J=1.7, 12.0Hz), 4.29 (1H, d, J=9.3Hz), 6.90-7.00 (2H, m), 7.13 (1H, s), 7.15-7.25 (2H, m), 7·45 (1H, dd, J=1.4, 8.3Hz), 7.80-7.90 (2K, m) 實施例7 OH 2.29 (3H, s), 3.35-3.55 (4H, m), 3.71 (1H, dd, J=5.1, 12.0Hz), 3.85-3.95 (lH, m), 4.15 (2H, s), 4.22 (lH, d, J=9.6Hz), 7.00-7.20 (5H, m), 7.43 (lH, dd, J=1.6, 8.2Hz), 7.75-7.85 (2H, m) 實施例8 3.35-3.55 (4H, m), 3.72 (lH, dd, J=5.6, 11.9Hz), 3.75 (3H, s), 3.85.3.95 (1H, m), 4.14 (2H, s), 4.23 (1H, d, J::9.2 Hz), 6.80-6.90 (2H, m), 7.09 (lH, s), 7.15-7.25 (2H, m), 7.43 (lH, dd, J=1.6, 8.1Hz), 7.75-7.85 (2H, m) 實施例9 1.20 (3H, t, J=7.6Hz), 2.60 (2H, q, J=7.6Hz), 3.35-3.55 (4H, m), 3.71 (lH, dd, J=5.2, 11.8Hz), 3.85-3.95 (1H, m), 4.16 (2H, s), 4.23 (lH, d, J=9.4Hz), 7.05*7.20 (5H, m), 7.43 (lH, dd, J=1.6, 8.5Hz), 7.75-7.85 (2H, m) 實施例10 OH 3.35-3.55 (4H, m), 3.72 (lH, dd, J=5.5, 12.0Hz), 3.85-3.95 (lH, m), 4.10 (2H, s), 4.23 (1H, d, J=9.3Hz), 6.65-6.75 (2H, m), 7.00-7.15 (3H, m), 7.43 (lH, dd, J=l.5, 8.3Hz), 7.75-7.85 (2H, m) 312XP/發明說明書(補件)/94·〇7/941〇6583 9。⑧ 1351400 [表2 ] 實施例編號化學結搆式 Ή-NMR (CD3OD) δ p pm 實施例11 OH 1.35 (3H, t, J=7.0He), 3.35-3.55 (4H, m), 3.65-3.75 (1H, m), 3.85-3.95 (1H, m), 3.99 (2H, q, J=6.9Hz), 4.13 (2H, s), 4.23 (1H, d, J=9.5Hz), 6.75-6.85 (2H, m), 7.09 (lH, s), 7.10-7.20 (2H, m), 7.43 (1H, dd, J=1.4, 8.4Ηε), 7.75-7.85 (2H, m) 實施例12 OH 2.20 (3H, d, J=1.4Hz), 3.35-3.55 (4H, m), 3.71 (1H, dd, J=5.4, 12.1Hz), 3.85' 3.95 (1H, m), 4.18 (2H, s), 4.23 (lH, d, J=9.6Hz), 6.85-6.95 (lH, m), 6.95-7.00 (1H, m), 7.12 (1H, t, J=8.0Hz), 7.17 (1H, s), 7.44 (1H, dd, J=1.4, 8.5Hz), 7.77 (1H, d, J=1H, d, J=1.4Hz), 7.84 (1H, d, J=8.5Hz) 實施例13 OH 2.29 (3H, s), 3.35-3.55 (4H, m), 3.71 (1H, dd, J=5.1, 12.3Hz), 3.85-3.95 (1H, m), 4.16 (2H, s), 4.23 (lH, d, J=9.4Hz), 6.95-7.20 (5H, m), 7.40-7.45 (1H, m), 7.75-7.85 (2H, m) 實施例Μ Η〇··'^γ^·'ΌΗ -Q OH 2.90-3.00 (2H, m), 3.05-3.15 (2H, m), 3.40-3.60 (4H, m), 3.76 (lH, dd, J=5.3, 11.9Hz), 3.90-3.95 (1H, m), 4.30 (1H, d, J=9.5Hz), 6.65-6.75 (2H, m), 7.00· 7.10 (2H, m), 7.14 (1H, s), 7.45 (lH, dd, J=1.7, 8.4Hz), 7.90-7.90 (2H, m) (實施例1 5 ) 第1步驟 6 -溴-1 -甲苯磺醯基-1 # -吲哚Example No. Chemical Structure 'H-NMR (CD3OD) «ppm Example 4 OH 3.35-3.55 (4H, m), 3.71 (lH, dd, J=5.4, 12.0 Hz), 3.89 (1H, dd, J =1.9, 12.0Hz), 4.21 (2H, s), 4.23 (1H, d, J=9.6Hz), 7.11 (1H, s), 7.15-7.30 (5H, m), 7.43 (1H, dd, J= 1.5, 8.2Hz), 7.81 (lH, d, J=1.5Hz), 7.83 (1H, d, J=8.2Hz) 贲Example 5 1 Q Os 2.90-3.05 (2H, m), 3.05-3.20 (2H , m), 3.40-3.60 (4H, m), 3.70-3.80 (4H, m), 3.85-3.95 (1H, m), 4.29 (lH, d, J=9.3 Hz), 6.75-6.85 (2H, m ), 7.05-7.15 (3H, m), 7.44 (lH, dd, J=1.4, 8.3Hz), 7.75-7.85 (2H, m) Example 6 Η〇"'ίΝγ^··*ΟΗ K 3.00- 3.10 (2H, m), 3.10-3.20 (2H, m), 3.40-3.55 (4H, m), 3.74 (lH, dd, J=5.3, 12.0Hz), 3.91 (1H, dd, J=1.7, 12.0 Hz), 4.29 (1H, d, J=9.3Hz), 6.90-7.00 (2H, m), 7.13 (1H, s), 7.15-7.25 (2H, m), 7·45 (1H, dd, J= 1.4, 8.3 Hz), 7.80-7.90 (2K, m) Example 7 OH 2.29 (3H, s), 3.35-3.55 (4H, m), 3.71 (1H, dd, J=5.1, 12.0Hz), 3.85- 3.95 (lH, m), 4.15 (2H, s), 4.22 (lH, d, J=9.6Hz), 7.00-7.20 (5H, m), 7.43 (lH, dd, J=1.6, 8.2Hz), 7.75 -7.85 (2H, m) Example 8 3.35-3.55 (4H, m), 3.72 (lH, dd, J=5.6, 11.9Hz), 3.75 (3H, s), 3.85.3.95 (1H, m), 4.14 (2H, s), 4.23 (1H, d, J::9.2 Hz), 6.80-6.90 (2H, m), 7.09 (lH, s), 7.15-7.25 (2H, m), 7.43 (lH, dd, J=1.6, 8.1Hz) , 7.75-7.85 (2H, m) Example 9 1.20 (3H, t, J=7.6Hz), 2.60 (2H, q, J=7.6Hz), 3.35-3.55 (4H, m), 3.71 (lH, dd , J=5.2, 11.8Hz), 3.85-3.95 (1H, m), 4.16 (2H, s), 4.23 (lH, d, J=9.4Hz), 7.05*7.20 (5H, m), 7.43 (lH, Dd, J=1.6, 8.5 Hz), 7.75-7.85 (2H, m) Example 10 OH 3.35-3.55 (4H, m), 3.72 (lH, dd, J=5.5, 12.0 Hz), 3.85-3.95 (lH , m), 4.10 (2H, s), 4.23 (1H, d, J=9.3Hz), 6.65-6.75 (2H, m), 7.00-7.15 (3H, m), 7.43 (lH, dd, J=l .5, 8.3Hz), 7.75-7.85 (2H, m) 312XP/Invention Manual (supplement)/94·〇7/941〇6583 9. 8 1351400 [Table 2] Example No. Chemical structural formula Ή-NMR (CD3OD) δ p pm Example 11 OH 1.35 (3H, t, J=7.0He), 3.35-3.55 (4H, m), 3.65-3.75 ( 1H, m), 3.85-3.95 (1H, m), 3.99 (2H, q, J=6.9Hz), 4.13 (2H, s), 4.23 (1H, d, J=9.5Hz), 6.75-6.85 (2H , m), 7.09 (lH, s), 7.10-7.20 (2H, m), 7.43 (1H, dd, J=1.4, 8.4Ηε), 7.75-7.85 (2H, m) Example 12 OH 2.20 (3H, d, J=1.4Hz), 3.35-3.55 (4H, m), 3.71 (1H, dd, J=5.4, 12.1Hz), 3.85' 3.95 (1H, m), 4.18 (2H, s), 4.23 (lH , d, J=9.6Hz), 6.85-6.95 (lH, m), 6.95-7.00 (1H, m), 7.12 (1H, t, J=8.0Hz), 7.17 (1H, s), 7.44 (1H, Dd, J = 1.4, 8.5 Hz), 7.77 (1H, d, J = 1H, d, J = 1.4 Hz), 7.84 (1H, d, J = 8.5 Hz) Example 13 OH 2.29 (3H, s), 3.35-3.55 (4H, m), 3.71 (1H, dd, J=5.1, 12.3Hz), 3.85-3.95 (1H, m), 4.16 (2H, s), 4.23 (lH, d, J=9.4Hz) 6.5. m), 3.05-3.15 (2H, m), 3.40-3.60 (4H, m), 3.76 (lH, dd, J=5.3, 11.9Hz), 3.90-3.95 (1H, m), 4.30 (1H, d, J=9.5Hz), 6.65 -6.75 (2H, m), 7.00· 7.10 (2H, m), 7.14 (1H, s), 7.45 (lH, dd, J=1.7, 8.4Hz), 7.90-7.90 (2H, m) (Example 1 5) Step 1 6 - Bromo-1 -toluenesulfonyl-1 # -吲哚

在 0 °C下加入氫化鈉（5 5 %，0 . 2 3 g )於 6 -溴-1 # -。引哚 (l.Og)之二甲基甲醯胺（10mL)溶液中，攪拌5分鐘。於混合物中加入曱苯磺醯氣（0 . 9 7 g )，於室溫下攪拌2 小時。將反應混合物注入水中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸錢乾燥。於減壓下餾除溶劑，將正己烷與二乙醚以2 / 1之比例加入殘渣，濾取固體後，於減壓下乾燥，得到標題化合物（1 . 2 g )。第2步驟 1-(1- 甲笨磺醯 -\H-。引哚 -6 - 基）-1 - 去 91 3 ] 2XP/發明說明書(補件)/94-07/94〗06583 1351400 氧-2, 3, 4, 6 -四-苄基/3 - D-葡哌喃聚糖在- 78°C下加入正丁基鋰（2.71mol/L 四氫呋喃溶液， 0 . 2 6 m L )於 6 -溴-1 -甲苯磺醯基-1 "-吲哚（0 · 2 5 g )之四氫°夫喊（8mL)溶液中，搜拌 5 分鐘。在-78 °C下加入 2,3,4,6,四-夕-苄基-D -葡萄糖酸-1,5 -内酯（0.39g) 之四氫呋喃（2 m L )溶液，於0 °C下攪拌3 0分鐘。將反應混合物注入飽和氯化銨水溶液中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥。於減壓下Sodium hydride (5 5 %, 0.23 g) was added to 6-bromo-1 # - at 0 °C. A solution of (1. Og) in dimethylformamide (10 mL) was stirred for 5 minutes. Toluene benzenesulfonate (0.97 g) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and saturated brine and dried over anhydrous sulfuric acid. The solvent was evaporated under reduced pressure. EtOAc was evaporated. Step 2 1-(1-A sulfonamide-\H-. 哚-6-yl)-1 - Go to 91 3] 2XP/Invention Manual (supplement)/94-07/94〗06583 1351400 Oxygen- 2, 3, 4, 6 -Tetrabenzyl/3-D-glucopyranan was added at -78 ° C to n-butyllithium (2.71 mol/L tetrahydrofuran solution, 0.66 m L) at 6 -Bromo-1 -toluenesulfonyl-1 "-吲哚(0 · 2 5 g ) in tetrahydrohypox (8 mL) solution, mix for 5 minutes. A solution of 2,3,4,6, tetra-oxime-benzyl-D-glucono-1,5-lactone (0.39 g) in tetrahydrofuran (2 m L) at 0 ° C was added at -78 °C. Stir for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Under reduced pressure

餾除溶劑，將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯=3 / 1 )精製，得到標題化合物（0 . 2 8 g )。第 3步驟 1 - (1 -甲笨醯基 - 1 Η - 。弓1 。朵 -6 - 基 ) -2,3,4,6 四 -0 -苄基 D - 葡〇底口南聚糖在- 2 o°c 下加入二氟化硼 •二乙醚錯合物 (0. 〇53g) 1-(1- 甲苯磺醯基 -\ Η -。弓I哚 -6 - 基）-]-去氧-2, 3, 4, 6 -四-苄基冷-D -葡哌喃聚糖（0.28g) 及三乙基矽烷（0.68g)之乙腈（4mL)溶液中，於室溫下攪拌 3 0分鐘。加入飽和碳酸鉀水溶液於反應混合物中，以二乙麵萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥。於減壓下餾除溶劑，將殘渣以矽膠管柱色層分析法（正己烷/醋酸乙酯=6 / 1〜4 / 1 )精製，得到標題化合物 (〇· 19g)。 Ή - NMR (CDC1 3) <5 ppm： 2. 2 1 (3H, s), . 3. 5 0 - 3. 6 0 ( 1 H, m ), 3. 6 0 - 3. 7 0 ( 2 Η, m ), 312ΧΡ/發明說明書(補件)/94-〇7/94106583 92 ⑧ 1351400 3. 7 5 - 3. 9 0 ( 4 H, m), 4. 26( 1 H, d, J = 10. 5Hz), 4. 36(1H, d, J = 9. 4Hz), 4. 59( 1 H, d, J = 12. 2Hz), 4. 67( 1 H, d, J = 10.8Hz), 4. 69 ( 1 H, d, J = 12.2Hz), 4. 90( 1 H, d, J = 10.7Hz), 4. 90( 1 H, d, J = 11. 1Hz), 4. 94(1H, d, J = 11. 0Hz), 6. 6 0 - 6. 7 0 ( 1 H, m ), 6. 8 0 - 6. 8 5 ( 2 H, m ), 7. 00-7. 18(5H, m), 7. 2 0 - 7. 4 5 ( 1 6 H, m ), 7. 5 4 - 7. 5 5 ( 1 H, m), 7. 5 5 - 7. 6 0 ( 1 H, m), 7. 6 5 - 7. 7 5 ( 2 H, m) , 8. 10-8. 15( 1 H, m ) 第4步驟 * 1- (1β-。引哚-6 -基）-1-去氧-2,3,4,6-四-0 -苄基-泠-D -葡哌喃聚糖The solvent was evaporated, and the residue was purified mjjjjlililililililililililililililililili Step 3 - 1 - (1 - Alum-based - 1 Η - . . . 1 - -6 - yl) - 2, 3, 4, 6 - 4 - benzyl D - glucosinolate - 2 o °c under the addition of boron difluoride and diethyl ether complex (0. 〇53g) 1-(1-toluenesulfonyl-\ Η-. bow I哚-6-yl)-]-deoxygenation -2,3,4,6-tetra-benzyl cold-D-glucosamine (0.28g) and triethyl decane (0.68g) in acetonitrile (4mL), stirred at room temperature 3 0 minute. A saturated aqueous solution of potassium carbonate was added to the mixture and the mixture was extracted. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted elut elut elut elut elut elut Ή - NMR (CDC1 3) <5 ppm: 2. 2 1 (3H, s), . 3. 5 0 - 3. 6 0 ( 1 H, m ), 3. 6 0 - 3. 7 0 ( 2 Η, m ), 312ΧΡ / invention specification (supplement) /94-〇7/94106583 92 8 1351400 3. 7 5 - 3. 9 0 ( 4 H, m), 4. 26 ( 1 H, d, J = 10. 5Hz), 4. 36(1H, d, J = 9. 4Hz), 4. 59( 1 H, d, J = 12. 2Hz), 4. 67( 1 H, d, J = 10.8Hz) , 4. 69 ( 1 H, d, J = 12.2 Hz), 4. 90 ( 1 H, d, J = 10.7 Hz), 4. 90 ( 1 H, d, J = 11. 1 Hz), 4. 94 (1H, d, J = 11. 0Hz), 6. 6 0 - 6. 7 0 ( 1 H, m ), 6. 8 0 - 6. 8 5 ( 2 H, m ), 7. 00-7. 18(5H, m), 7. 2 0 - 7. 4 5 ( 1 6 H, m ), 7. 5 4 - 7. 5 5 ( 1 H, m), 7. 5 5 - 7. 6 0 ( 1 H, m), 7. 6 5 - 7. 7 5 ( 2 H, m) , 8. 10-8. 15( 1 H, m ) Step 4 * 1- (1β-. 哚-6 - -1 -deoxy-2,3,4,6-tetra--0-benzyl-indole-D-glucopyran

加入氫氧化鉀（0 . 2 7 g )於 1 - ( 1 -曱笨磺醯基-1 # -吲哚-6-基）-1-去氧-2, 3, 4, 6 -四-0-苄基冷- D-葡略喃聚糖（0.19g)之乙醇（4mL)及四氫咳喃（lmL)溶液中，於5 0 °C下攪拌1夜。加入鹽酸水溶液（2 m ο 1 / L，6 m L ) 於反應混合物中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥。於減壓下餾除溶劑，將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯 =3 / 1〜3 / 2 )精製，得到標題化合物（0 . 1 3 g )。 Η - NMR ( CDC 13) <5 ppm : 3. 55-3. 68 ( 2H, m), 3.70(1H, d, J=10.6Hz), 3. 7 5 - 3. 9 0 ( 4H, m), 4.30C1H, d, J=10.6Hz)’ 4.35(1H, d, J=9.4Hz), 4.57C1H, d, J=12.4Hz), 4.66(1H, d, J=10.7Hz), 4.68(1H, d, J=12.4Hz), 4.89(1H, d, J=10.7Hz), 4.90(1H, d, J=ll.lHz), 4.97(1H, d, 3 ] 2XP/發明說明書(補件)/94-07/94106583 93 ⑧ 1351400 J = 11.1Hz), 6. 54-6. 60(1H, m), 6. 80-6. 90(2H, m), 7. 05-7. 40 ( 1 9H, m), 7. 45-7. 50 ( 1 H, m), 7. 60-7. 70 ( 1 H, m), 8. 10-8. 20(1H, m) 第5步驟 1 - [ 1 - (4 -曱苄基）-1^-。弓 I 哚-6 -基]-1 -去氧-2,3,4,6 -四-苄基冷-D-葡哌喃聚糖Add potassium hydroxide (0.77 g) to 1 - (1 - oxasulfonyl-1 #-吲哚-6-yl)-1-deoxy-2, 3, 4, 6 - four-0 To a solution of benzyl cold-D-glucomannan (0.19 g) in ethanol (4 mL) and tetrahydromethane (1 mL) was stirred at 50 ° C overnight. Aqueous hydrochloric acid (2 m ο 1 / L, 6 m) was added to the mixture and the mixture was evaporated. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjj . Η - NMR ( CDC 13) <5 ppm : 3. 55-3. 68 ( 2H, m), 3.70 (1H, d, J = 10.6 Hz), 3. 7 5 - 3. 9 0 ( 4H, m ), 4.30C1H, d, J=10.6Hz)' 4.35(1H, d, J=9.4Hz), 4.57C1H, d, J=12.4Hz), 4.66(1H, d, J=10.7Hz), 4.68( 1H, d, J = 12.4 Hz), 4.89 (1H, d, J = 10.7 Hz), 4.90 (1H, d, J = ll.lHz), 4.97 (1H, d, 3) 2XP/invention specification (supplement) ) /94-07/94106583 93 8 1351400 J = 11.1Hz), 6. 54-6. 60(1H, m), 6. 80-6. 90(2H, m), 7. 05-7. 40 ( 1 9H, m), 7. 45-7. 50 ( 1 H, m), 7. 60-7. 70 ( 1 H, m), 8. 10-8. 20(1H, m) Step 5 - [ 1 - (4-indolyl)-1^-. Bow I 哚-6 -yl]-1 -deoxy-2,3,4,6-tetra-benzyl cold-D-glucopyran

在0°C下加入氫化鈉（60%’0.01g)於1_ (1τ7_ °弓丨°朵_ 6-基）-1-去氧- 2,3,4,6 -四-节基-yS _D -葡0底鳴聚糖（0.13g)之夂/V-二甲基甲醯胺（2mL)溶液中，攪拌10 分鐘。於混合物中加入 4 -曱基苄基氯（0 . 0 3 2 g )，於室溫下攪拌2小時。將反應混合物注入水中，以二乙醚萃取。將有機層用水及飽和食鹽水洗淨，並以無水硫酸鎂乾燥。於減壓下餾除溶劑，將殘渣以矽膠管柱色層分析法（洗提溶劑：正己烷/醋酸乙酯=5 / 1 ) 精製，得到標題化合物 (〇·12g)。 Ή - NMR (CDC13) 5 ppm : 2. 27(3H, s), 3. 5 0 - 3. 6 5 ( 3 H, m), 3. 7 0 - 3. 9 0 ( 4 H, m ), 4. 22(1H, d, J = 10.2Hz), 4. 31(1H, d, J = 9.5Hz), 4. 54(1H, d, J = 12. 3Hz), 4 . 6 0 - 4. 7 0 ( 2 H, m), 4. 88(1H, d, J = 10.6Hz)，4. 94(1H, d, J = 10. 7Hz ), 5. 23(2H, s ), 6. 50-6. 55(1H, m), 6. 7 5 - 6. 8 5 ( 2 H, m), 6. 90-7. 00( 2H, m ), 7. 0 0 - 7. 0 5 ( 2 H, m ), 7. 0 5 - 7. 4 0 ( 3 1 H, m ) , 7. 6 4 - 7. 6 8 ( 1 H, m ) 第6步驟 94⑧ 312XP/發明說明書(補件)/9小07/94106583 1351400 1 - [ 1 ~ (4 -曱节基）-1"-。弓 I 。朵-6 -基]-1-去氧-召-D-葡哌喃聚糖在氫氣環境下，於室溫中將1 - [ 1 - ( 4 -曱苄基）-1及-°引0朵 -6 - 基 ]-1_ 去氧 -2，3,4，6_ 四 -0 - 苄基-/3 - D -葡哌喃聚糖及 10%鈀碳粉末（0.12g)之四氫呋喃（3 m L )及甲醇（3 m L )溶液攪拌1小時。濾除不溶物，將濾液於減屋下濃縮。將殘造以石夕膝管柱色層分析法（洗提溶劑：氯化曱烷/甲醇=1 0 / 1 ) 精製，得到標題化合物Sodium hydride (60% '0.01g) was added at 0 ° C at 1_(1τ7_ ° 丨 ° _ 6-yl)-1-deoxy-2,3,4,6-tetra-knot-yS _D - A solution of glucosinolate (0.13 g) in hydrazine / V-dimethylformamide (2 mL) was stirred for 10 minutes. To the mixture was added 4-mercaptobenzyl chloride (0.32 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjlililililililililililililililili Ή - NMR (CDC13) 5 ppm : 2. 27(3H, s), 3. 5 0 - 3. 6 5 ( 3 H, m), 3. 7 0 - 3. 9 0 ( 4 H, m ), 4. 22(1H, d, J = 10.2Hz), 4. 31(1H, d, J = 9.5Hz), 4. 54(1H, d, J = 12. 3Hz), 4. 6 0 - 4. 7 0 ( 2 H, m), 4. 88 (1H, d, J = 10.6Hz), 4. 94(1H, d, J = 10. 7Hz ), 5. 23(2H, s ), 6. 50 -6. 55(1H, m), 6. 7 5 - 6. 8 5 ( 2 H, m), 6. 90-7. 00( 2H, m ), 7. 0 0 - 7. 0 5 ( 2 H, m ), 7. 0 5 - 7. 4 0 ( 3 1 H, m ) , 7. 6 4 - 7. 6 8 ( 1 H, m ) Step 6 948 312XP / Invention Manual (supplement) / 9 small 07/94106583 1351400 1 - [ 1 ~ (4 - 曱节基)-1"-. Bow I. -6-6-yl]-1-deoxy-callo-D-glucopyranose 1- 1 [(4- benzyl)-1 and -° in a hydrogen atmosphere at room temperature -6-yl]-1_deoxy-2,3,4,6_tetra-O-benzyl-/3-D-glucopyranan and 10% palladium on carbon powder (0.12 g) in tetrahydrofuran (3 m L ) and methanol (3 m L) solution were stirred for 1 hour. The insoluble material was filtered off, and the filtrate was concentrated under reduced room. The residue was purified by Shixia Knee column chromatography (eluent solvent: decane/methanol = 10 / 1) to give the title compound

(0· 0 3 5 g ) ° Ή - NMR (CDaOD) δ ppm ： 2. 27(3H, s)，3 • 30 -3. 55(4H, m : ), 3. 69(1 H, d d , J 5.3, 12.0Hz)， 3.87( 1H, d d , J = 1 . 7, 1 2. 0Hz) ，4. 12(1H, d, J = 8. 9H z ), 5.： 34(2H, s ), 6 .44- 6 . 47(1H, m ), 7. 0 0 - 7. 0 5 ( 2 H, m ), 7. 05-7. 1 〇( 2H j m ), 7. 13( 1 H, dd, J =1.2， 8 .0Hz), 7. 2 2 ( 1 H, d, J = 3 · 2Hz) » 7. 42(1H, m ), 7. 53(1 Η, d , J = =8. 1 Hz ) 表3所記載之化合物，可與上述實施例記載之相同方法製造。 95 312XP/發明說明書(補件)/94-07/941065S3 1351400(0· 0 3 5 g ) ° Ή - NMR (CDaOD) δ ppm : 2. 27(3H, s), 3 • 30 -3. 55(4H, m : ), 3. 69(1 H, dd , J 5.3, 12.0 Hz), 3.87 ( 1H, dd , J = 1 . 7, 1 2. 0 Hz) , 4. 12 (1H, d, J = 8. 9H z ), 5.: 34(2H, s ) , 6 .44- 6 . 47(1H, m ), 7. 0 0 - 7. 0 5 ( 2 H, m ), 7. 05-7. 1 〇( 2H jm ), 7. 13( 1 H, Dd, J = 1.2, 8 .0 Hz), 7. 2 2 ( 1 H, d, J = 3 · 2 Hz) » 7. 42(1H, m ), 7. 53(1 Η, d , J = =8 1 Hz) The compounds described in Table 3 can be produced in the same manner as described in the above examples. 95 312XP/Invention Manual (supplement)/94-07/941065S3 1351400

(試驗例1 ) 人體S G L Τ 1活性抑制作用確認試驗 (1)選殖人體SGLT1及表現載體之基因重組將人體小腸來源之全RNA(total RNA)(0ri gene公司製品）以寡去氧胸腺核苷（oligodT)為引子進行反轉錄’製成 PCR放大用cDNA基因庫。以此cDNA基因庫為模板，用PCR 法放大 Hediger 等報告之人體 SGLT1(ACCESSI0N:M24847) 之第 1 至第 2005 之鹼基序列’並插入於 pcDNA3.]( — )(Invitrogen公司製品）之多選殖位點 312XP/發明說明書(補件)/94-07/94】06583(Test Example 1) Confirmation test for inhibition of activity of human SGL Τ 1 (1) Recombination of human SGLT1 and expression vector Recombination of human total intestinal RNA (total RNA) (product of 0 ri gene) with oligo-thyron nucleus The oligodT is reverse-transcribed into a primer to make a cDNA gene library for PCR amplification. Using this cDNA gene library as a template, PCR was used to amplify the base sequences 1 to 2005 of human SGLT1 (ACCESSI0N: M24847) reported by Hediger et al. and inserted into pcDNA3.](-) (product of Invitrogen) Colonization site 312XP / invention manual (supplement) /94-07/94]06583

1351400 (Multiple Cloning Site)。所插入之DMA驗基序列與報告之鹼基序列為完全相同。 (2)確立人體SGLT1安定表現株人體SGLT1表現載體以Sea I消化成直鏈狀DNA後，脂轉染法（lipofection) (Effectene Transfecti Reagent: QIAGEN)導.入至 CH0-K1 細胞中。使用 G4 1 m g / m L ( L I F E T E C N 0 L 0 G I E S公司製品）獲得新黴素耐性胞株，並用後述方法測定曱基-a - D -葡萄糖吡喃苷之取活性。選取顯示最大攝取活性之株作為 C S 1 - 5 - 1 1 D 隨後在20〇Aig/mL之G418存在下培養。 (3)測定甲基-a - D-葡萄糖。比喃苦（〇: - MG)攝取之制活性 C S 1 - 5 - 1 1 D細胞株以每孔3 X 1 0 4個之濃度接種於9 6 微量培養盤，經培養2日後供攝取實驗之用。攝取用緩液（含 140mM氣化納、2mM氣化鉀、lmM氯化妈、ImM氣 φ 鎂、1 0 m Μ 2 - [ 4 - ( 2 -羥乙基）-1 -哌畊基]乙磺酸、5 三（羥甲基）胺基曱烷之緩衝液，ρ Η 7 . 4 )中混合添加有非射性標識體（S i g m a 公司製品）與 C 14標識體（A m e r s h 卩1131_1113(^381〇七6(：}1公司製品）之0：-讨6混合物，其最終度調整為 1 m Μ。試驗化合物溶解於二曱亞砜後，用蒸餾適當稀釋後添加入於含有ImMa -MG之攝取用緩衝液， - 為測定用缓衝液。對照組為不含試驗化合物之測定用緩液，而基礎攝取測定用則以1 4 0 m Μ氣化膽鹼取代氯化鈉製基礎攝取測定用緩衝液。將上述培養之CS1之培養基已以 on 18 細攝 ) 抑孔衝化 m Μ 放 am 濃水即衝調去 312XP/發明說明書(補件)/94-07/941065S3 97 ⑧ 1351400 除，每孔加入180//L前處理用缓衝液（不含a - MG之基礎攝取測定用緩衝液），於3 7 °C靜置1 0分鐘。此操作再重複 1次後，去除前處理用缓衝液，每孔各加入7 5 // L測定用緩衝液或基礎攝取用緩衝液，於3 7 °C靜置。1小時後去除測定用緩衝液，每孔以1 8 0 // L清洗用緩衝液（含1 0 m Μ非放射性標識體a - M G之基礎攝取測定用緩衝液）洗淨2次。隨後每礼加入7 5 // L之0 . 2 m ο 1 / L氩氧化納以溶解細胞，移動此細胞溶液於P i c 〇 - P 1 a t e ( P a c k a r d公司製品）。加入1351400 (Multiple Cloning Site). The inserted DMA sequence is identical to the reported base sequence. (2) Establishment of human SGLT1 stable expression strain The human SGLT1 expression vector was digested into linear DNA by Sea I, and then introduced into CH0-K1 cells by lipofection (Effectene Transfecti Reagent: QIAGEN). A neomycin-resistant cell strain was obtained using G4 1 m g / m L (product of L I F E T E C N 0 L 0 G I E S company), and the activity of thiol-a-D-glucopyranoside was measured by the method described later. The strain showing the maximum uptake activity was selected as C S 1 - 5 - 1 1 D and subsequently cultured in the presence of 20 〇 Aig/mL of G418. (3) Determination of methyl-a-D-glucose. The active CS 1 - 5 - 1 1 D cell strain inoculated with sputum (〇: - MG) was inoculated into 9 6 microplates at a concentration of 3 X 104 per well, and was ingested for 2 days after culture. use. Ingestion slow solution (containing 140 mM gasified sodium, 2 mM potassium carbonate, lmM chlorinated mother, 1 mM gas φ magnesium, 10 m Μ 2 - [ 4 - ( 2 -hydroxyethyl)-1 - piperage] A buffer of sulfonic acid or 1,3-(hydroxymethyl)amino decane, ρ Η 7.4 ) is mixed with an injectable marker (product of Sigma Co., Ltd.) and a C 14 marker (A mersh 卩 1131_1113 ( ^381〇七6(:}1 Company's product) 0:- _ 6 mixture, the final degree is adjusted to 1 m Μ. The test compound is dissolved in disulfoxide, diluted with distilled and then added to contain ImMa - The buffer for ingestion of MG, - is the buffer for measurement. The control group is a slow solution for the measurement without the test compound, and the basal uptake measurement is based on the use of 1400 g of choline instead of sodium chloride. The buffer for the measurement. The culture medium of the above-mentioned cultured CS1 has been finely photographed on 18). The concentration of the medium of the above-mentioned CS1 is reduced to m Μ. The concentration of water is adjusted to 312XP/invention specification (supplement)/94-07/941065S3 97 8 1351400 In addition, 180//L pre-treatment buffer (without a-MG base uptake assay buffer) was added to each well and allowed to stand at 3 7 °C for 10 ° After repeating this operation once more, the pretreatment buffer was removed, and 7 5 // L of assay buffer or basal uptake buffer was added to each well and allowed to stand at 37 ° C. The assay was removed after 1 hour. Wash the buffer twice with 1 0 0 // L of washing buffer (containing 10 m Μ non-radioactive label a- MG based uptake assay buffer) for each well. Then add 7 5 / / L of 0. 2 m ο 1 / L argon oxide to dissolve the cells, and move the cell solution to P ic 〇- P 1 ate (product of P ackard).

150// L 之 Microscint-40 (Packard 公司製品）並混合後，以微量閃標計數器 TopCount (Microscintillation counter，Packard 公司製品）測定放射活性。以對照組之攝取量減去基本攝取量之值為1 0 0 %，計算試驗化合物各濃度之甲基-a - D -葡萄糖吡喃苷攝取量。以對元標繪 (logitplot)計算試驗化合物抑制50%曱基-a - D-葡萄糖吡喃苷之攝取的濃度（I C 5。值）。結果如表4所示。 •[表 4] 試驗化合物 I Cso 值（"Μ ) 實施例 1 1 . 5 (試驗例2 ) 人體S G L Τ 2活性抑制作用確認試驗 (1)選殖人體SGLT1及表現載體之基因重組將人體腎臟來源之全 RNA (Ori gene公司製品）以寡去氧胸腺核苷為引子進行反轉錄，製成PCR放大用cDNA基因庫。以此cDNA基因庫為模板，用PCR法放大R.G. Wells 3 ] 2XP/發明說明書(補件)/94-07/94106583 98 ⑧ 1351400 等報告之人體 SGLT2UCCESSI0N: M95549、M95299)之第 2 至第 2039 之驗基序列（base sequence)，並插入於 pcDNA3. 1( — )(Invitrogen公司製品）之多選殖位點。此所插入之DNA鹼基序列與已報告之鹼基序列為完全相同。 (2)確立人體SGLT2安定表現株人體SGLT2表現載體以Sea I消化成直鏈狀DNA後，以脂轉染法（lipofection) (Effectene TransfectionAfter 150//L of Microscint-40 (product of Packard Company) and mixed, the radioactivity was measured with a micro-flash counter TopCount (Microscintilation counter, manufactured by Packard Company). The intake of methyl-a-D-glucopyranoside at each concentration of the test compound was calculated by subtracting the value of the basic intake from the control group by 100%. The concentration at which the test compound inhibited the uptake of 50% thiol-a-D-glucopyranoside (I C 5 value) was calculated by logitplot. The results are shown in Table 4. • [Table 4] Test compound I Cso value ("Μ) Example 1 1.5 (Test Example 2) Human SGL Τ 2 Activity inhibition confirmation test (1) Genetic recombination of human SGLT1 and expression vector Total RNA derived from the kidney (product of Ori Gene Co., Ltd.) was reverse transcribed using oligo-thymidine as a primer to prepare a cDNA gene library for PCR amplification. Using the cDNA gene library as a template, the RG Wells 3] 2XP/invention specification (supplement)/94-07/94106583 98 8 1351400, etc. reported by human body SGLT2UCCESSI0N: M95549, M95299) 2nd to 2039 The base sequence was inserted and inserted into multiple selection sites of pcDNA3.1 (() (product of Invitrogen). The inserted DNA base sequence is identical to the reported base sequence. (2) Establishing the human SGLT2 stable expression strain The human SGLT2 expression vector is digested into a linear DNA by Sea I, and then subjected to lipofection (Effectene Transfection).

Reagent: QIAGEN)導入至 CH0 - K1 細胞中。使用 G418 1 m g / m L ( L I F E T E C Ν 0 L 0 G I E S公司製品）獲得新黴素耐性細胞株’並用後述方法測定甲基-α - D -葡萄糖吡喃苷之攝取活性。選取顯示最大攝取活性之株作為CS2 - 5Ε，隨後在200/zg/mL之G418存在下培養。 (3 )測定甲基-a _ D -葡萄糖吡喃苷（α _ μ G )攝取之抑制活性 C S 2 - 5 Ε細胞株以每礼3 X 1 〇 4個之濃度接種於9 6孔微量 ^ 培養盤，經培養2日後供攝取實驗之用。攝取用緩衝液（含 140mM氣化納、2mM氣化鉀、lmM氯化鈣、氯化鎂、i〇mM 2 - [ 4 - ( 2 -羥乙基）-1 _哌畊基]乙磺酸、5mM三（羥曱基）胺基甲烷之緩衝液，ρ Η 7 · 4 )中混合添加有非放射性標識體（Sigma 公司製。。）與 C 標識體（Amersham Pharmacia ' Biotech公司製品）之α _ MG混合物，其最終濃度調整為 -1 m M。試驗化合物溶解於二甲亞颯後，用蒸餾水適當稀釋後添加入於含有1 m Μ - M G之攝取用緩衝液，即為測定用緩衝液。對照組為不含試驗化合物之測定用緩衝液，而基礎 312ΧΡ/發明說明書(補件)/94-07/94106583 99 ⑧ 1351400Reagent: QIAGEN) was introduced into CH0 - K1 cells. A neomycin-resistant cell strain was obtained using G418 1 m g / m L (product of L I F E T E C Ν 0 L 0 G I E S company), and the activity of methyl-α-D-glucopyranoside was measured by the method described later. The strain showing the maximum uptake activity was selected as CS2 - 5 , and then cultured in the presence of 200 / zg / mL of G418. (3) Determination of the inhibitory activity of methyl-a-D-glucopyranoside (α _ μ G ) uptake CS 2 - 5 Ε cell line was inoculated into 96 wells at a concentration of 3 X 1 〇 4 per litre ^ The culture plate was used for ingestion experiments after 2 days of culture. Buffer for ingestion (containing 140 mM sodium hydride, 2 mM potassium hydride, lmM calcium chloride, magnesium chloride, i mM 2 - [ 4 - (2-hydroxyethyl)-1 _ piperylene] ethanesulfonic acid, 5 mM A buffer of tris(hydroxyindenyl)aminomethane, ρ Η 7 · 4 ) was mixed with a non-radioactive label (manufactured by Sigma) and a C marker (product of Amersham Pharmacia 'Biotech) α _ MG The final concentration of the mixture was adjusted to -1 m M. The test compound was dissolved in dimethyl hydrazine, diluted with distilled water, and added to an ingestion buffer containing 1 m Μ - M G , which was used as a buffer for measurement. The control group is the assay buffer containing no test compound, and the base 312ΧΡ/invention specification (supplement)/94-07/94106583 99 8 1351400

攝取測定用則以1 4 0 m Μ氣化膽鹼取代氯化鈉調製基礎攝取測定用緩衝液。將上述培養之細胞之培養基去除，每孔加入1 8 0 // L前處理用緩衝液（不含a - M G之基礎攝取測定用緩衝液），於3 7 °C靜置1 0分鐘》此操作再重複1次後，去除前處理用緩衝液，每孔各加入7 5 # L測定用緩衝液或基礎攝取用緩衝液，於3 7 °C靜置。1小時後去除測定用緩衝液，每礼以1 8 0 # L之清洗用缓衝液（含1 0 m Μ非放射性標識體a - M G之基礎攝取測定用緩衝液）洗淨2次。隨後每孔加入7 5 L之0 . 2 m ο 1 / L氫氧化納以溶解細胞，移動此細胞溶液於 Pic〇-Plate(Packard公司製品）。加入 150/iL 之 M i c r 〇 s c i n t - 4 0 ( P a c k a r d公司製品）並混合後，以微量閃爍計數器T 〇 p C 〇 u n t ( P a c k a r d公司製品）測定放射活性。以對照組之攝取量減去基本攝取量之值為1 0 0 %，計算試驗化合物各濃度之曱基-a - D -葡萄糖吡喃苷攝取量。以對元標繪計算試驗化合物抑制 5 0 %甲基-a - D -葡萄糖°比喃苷之攝取的濃度（I C η值）。結果如表5所示。 [表5] 試驗化合物 I C 5。值（η Μ ) 實施例 2 57 實施例 9 1.4 (產業上之可利用性）本發明之上述一般式（I )表示之縮合雜環衍生物、其藥理學上容許之鹽及該等之前驅藥，係表現抑制人體 SGLT 活性作用，能夠抑制小腸中之葡萄糖吸收或能夠抑制腎臟 312ΧΡ/發明說明書(補件)/94-07/94106583 100 ⑧ 1351400 再吸收葡萄糖，進而抑制血糖值之上升或使血糖值減低。因此，依據本發明，可提供優良之糖尿病' 飯後高血糖、葡萄糖耐性異常、糖尿病性併發症、肥胖症等因高血糖症引起之疾病之預防或治療劑。For the uptake assay, the buffer for the basic uptake assay was prepared by substituting sodium chloride for 1 40 m Μ choline. The medium of the cultured cells was removed, and 180 k of L pretreatment buffer (without a-MG base uptake assay buffer) was added to each well, and allowed to stand at 37 ° C for 10 minutes. After the operation was repeated once more, the pretreatment buffer was removed, and 75 5 L of the measurement buffer or the basal ingestion buffer was added to each well, and the mixture was allowed to stand at 37 ° C. After 1 hour, the measurement buffer was removed, and each rinse was washed twice with a washing buffer (containing 10 m Μ non-radioactive label a-M G base uptake assay buffer) of 180 μL. Then, 75 L of 0. 2 m ο 1 / L of sodium hydroxide was added to each well to dissolve the cells, and the cell solution was moved to a Pic〇-Plate (product of Packard Co.). After 150/iL of M i c r 〇 s c i n t - 4 0 (product of P a c k a r d) was added and mixed, the radioactivity was measured by a micro scintillation counter T 〇 p C 〇 u n t (product of P a c k a r d). The ingestion amount of the thiol-a-D-glucopyranoside at each concentration of the test compound was calculated by subtracting the value of the basic intake from the intake of the control group to 100%. The test compound was used to calculate the concentration (I C η value) of the test compound for inhibiting the uptake of 50% methyl-a-D-glucose. The results are shown in Table 5. [Table 5] Test compound I C 5 . Value (η Μ ) Example 2 57 Example 9 1.4 (Industrial Applicability) The condensed heterocyclic derivative represented by the above general formula (I) of the present invention, a pharmacologically acceptable salt thereof, and the like A drug that inhibits the activity of SGLT in the human body, inhibits glucose absorption in the small intestine, or inhibits kidney 312 ΧΡ / invention instructions (supplement) /94-07/94106583 100 8 1351400 reabsorbs glucose, thereby inhibiting the rise or The blood sugar level is reduced. Therefore, according to the present invention, it is possible to provide an agent for preventing or treating diseases caused by hyperglycemia such as hyperglycemia, postprandial hyperglycemia, abnormal glucose tolerance, diabetic complications, and obesity.

312ΧΡ/發明說明書(補件)/94-〇7/S>4106583 101 ⑧312ΧΡ/Invention Manual (supplement)/94-〇7/S>4106583 101 8

Claims

1351400 -π Announcement 10, the scope of application for patent _ MAR 1 4 2011 w years; month A repair (more) original replacement 1. A condensed heterocyclic derivative or its pharmacologically acceptable salt or such precursor , which is characterized by the following general formula (I): R3

R1 to R4 are each independently a hydrogen atom, a hydroxyl group, an amine group, a halogen atom, a Ci-6 alkyl group, a Ci-6 alkoxy group, a cyano group, a carboxyl group, a C2-7 alkoxycarbonyl group, an amine fluorenyl group, a single or two (Ci-6 alkane) amine group, functionalized (Ci-6 alkyl) group, hydroxy (Ci-6 alkyl) group, cyan (C丨-6 alkyl) group, carboxy (C丨-6 alkyl) group, C2- 7 alkoxycarbonyl (C丨-6 alkane) group, amine methyl (Cl-6) group, amine (Cl-6) group, mono or di(Cl-6) amine (Cl-6) base , (Ci-6 alkoxy) group, hydroxy (Ci-6 alkoxy) group, carboxy (Ci-6 alkoxy) group, C2-7 alkoxycarbonyl (1-6 alkoxy) group, amine formazan (Ci-6 alkoxy), amine (1-6 alkoxy), mono or di(C丨-6 alkyl)amine (Cl-6 alkoxy), C3-7 cycloalkyl, C3-7 ring Oxidized (C3-7 cycloalkyloxy) group, C3-7 ring (Ci-6) group or C3-7 cycloalkane (Cl-6 alkoxy) group; R5 and R6 are each independently a hydrogen atom, a hydroxyl group, a halogen atom, Ci-6 alkyl, C2-6 dilute, C2-6 alkynyl group, Ci-6 alkoxy group, C2-6 dilute oxygen (C2-salkenyloxy) group, Ci-6 sulphur group, C2-6 Solder sulfur-based, halogenated (Ci-6) base, halogenated (C1-6 oxygenated) base, halogen (C1-6 Institute sulfur), by (C1-6) base, by (C2-6) base, by (Cl-6 oxy) base, by (Cl-6 sulfur) base, rebel Carboxylic acid (Ci-6 alkyl) group, carboxy (C2-6 alkene) group, carboxy (Ci-6 alkoxy) group, carboxy (Ci-6 102 94106583 1351400 alkylthio) group, C2-7 alkoxycarbonyl group, C2 -7 alkoxycarbonyl (Ci-6 alkyl) group, C2-7 alkoxycarbonyl (C2-6 alkene) group, C2-7 alkoxycarbonyl (Ci-6 alkoxy) group, C2-7 alkoxycarbonyl (Ci -6 sulphur-based), Cl-6-sintered succinctyl, Cl-6 succinct-'-UVWN(R7)-Z or may have 1~3 groups selected from the following substituent group α The following substituents (i) to (xi i ) as a ring substituent: (i) C 6 - 1 0 aryl, (ii) C 6 - 1 C aryl _ 0 -, ( iii ) C 6 - 1 0 aryl-S -, (i V ) C 6 -: 10 aryl (Cl-6 炫) group ' '(V )Ce -1 〇芳(C1' -6: gas), (vi)C 6 - 1 (aryl (Cl-6 alkylthio) group, (V ii ) C3-7 cycloalkyl ' ( viii ) C 3 -7 cycloalkyl-0 - , (i X ) C 3 -7 cycloalkyl -S -, (X) C: 3 - 7 naphthenic (C 1-6 ) base, (X i ) C3-· [Circular (C丨-6 alkoxy) Or (X i i) C 3 - 7 cycloalkyl (Cl-6-hyun thio);

u is -〇-, -S- or a single bond (but when u is -〇- or -S-, V and W are not a single bond at the same time); V is a C!-6 alkyl group which may have a hydroxyl group, C2-6 extends an alkenyl group or a single bond; W is -CO-, -S〇2-, -C(==NH)- or a single bond; Z is a hydrogen atom, a C2-7 alkoxycarbonyl group, a C6-!. Aromatic (C2-7 alkoxycarbonyl), fluorenyl, -RA, -C0RB, -S〇2Rb, -C0N(Rc)Rd, -CSN(Rc)Rd, -S(hNHRA or -C(= NRE N(RF)RC; R7, RA, Rc and RD are each independently a hydrogen atom, and may have 1 to 5 alkyl groups selected from any group of the following substituent groups /3 or may have 1~ 3 substituents (xiii) to (xiv) selected from any of the following substituent groups a: (xiii) Ce-i. aryl or (xiv) C3-7 cycloalkyl; RB is C2 -7 Oxygen-removing group, Cl-6 calcining mercaptoamine group, C6-10 aromatic sulfhydryl group 103 94106583 1351400 Amine group> may have 1 to 5 options 1 Any group of the following substituent group β The C 1-6 pit group may have the following substituents ( XV ) to ( X vi ) • (XV ) C 6 •10 aryl or any group selected from the following substituent group α (xv i ) C3. -7 cycloalkyl* Re, rf and Re are each independently a hydrogen atom, a cyano group, an amine carbenyl group, a C 2 - 1 fluorenyl group C2 -7 : a hospital oxycarbonyl group, a Ce -10 aryl group ( C2- 7 alkoxycarbonyl) nitro, C 1 - £ fluorenyl, amine sulfonyl , carbarn imid 〇 y 1 . or · may have 15 5 i selected from any of the following substituent groups J3 of Cl- -6; decyl; or Re and RF bond forming Base » Q is - C 丨-6 stretching group -, - C 2 - 6 extending alkenyl group - C 2-6 stretching alkynyl group - - C. - 6 alkyl group - 0 - , - C 1 - 6 stretching Alkyl-S - , -0 - C 1 - 6 Stretching base - , -S_ Cl-6 stretching group -, -Cl- 6 stretching group - 0 - C 1 - 6 alkyl group - , -Cl - .6 炫炫- S -1 6 alkylene - • C0N(R8)- - N(R8)C0 — , -C 1-1 S

-C0N(R8)- or -C0N(R8)-C!-6 alkylene-R8 is a hydrogen atom or a Ch alkyl group; ring A is a C6-10 aryl group;

R9 is a hydrogen atom, C丨-6 alkyl 'hydroxy(C丨-6 alkyl) group 'C3-7 cycloalkyl group or C3-7 104 94106583 1351400 ring-burning (C 1 - 6 burning) group; G is a formula Eu

HO, 丫, OH OH (G-1) or

(G-2) E1 is a hydrogen atom, a fluorine atom or a hydroxyl group; E2 is a hydrogen atom, a fluorine atom, a fluorenyl group or a hydroxymethyl group; and the precursor drug is a condensed heterocyclic derivative represented by the general formula (I), a compound in which the 6-position hydroxyl group of the group represented by the formula (G-2) is substituted with a C2-7 alkoxycarbonyl group; [Substituent group α] a halogen atom, a hydroxyl group, an amine group, a Ci-6 alkyl group , 0-6 alkoxy group, dentate (Cn alkane) group, halogenated (C丨-6 alkoxy) group, hydroxy (C丨-6 alkyl) group, C2-7 alkoxycarbonyl (C丨-6院) Base, via (Cl-6 oxy-oxygen) group, amine (Cl-6) base, amine (Cl-6 alkoxy) group, mono or di(Cl-6) amine group, single or two -6 burned)] Amine, Cl-6 calcined base, Cl-6 calcined base amine, Cl-6 brilliant base amine (Cl-6) base, slow base, (: 2-7 Alkoxycarbonyl, aminoxime and -C0N(RH) R1; [Substituent group cold] Halogen atom, trans group, amine group, Cl-6 alkoxy group, Cl-6 sulphur group 'toothing (Cl -6 alkoxy), dentate (Ci-6 alkylthio), hydroxy (Ci-6 alkoxy), hydroxy (0-6 alkane 105 94106583 1351400 thio), amine (C!-6 alkoxy) Base, amine (Ci-6 alkyl sulfide Base, mono or di(Ci-6 alkane) amine group, mono or bis[hydroxy(Ci-6 alkane)] group, ureido group, sulfonamide group, mono or di(Ci-6 alkane)urea group, single Or bis[hydroxy(C,-6 alkane)]ureido, mono or di(Ci-6 炫), continuation of amine groups, mono- or di-[((Cl-6)), amine-based, C2- 7 alkylamino group, amine (C2-7 tyrosylamine) group, Cl-6 burning base, Cl-6 flavonoid amino group, amine hydrazine (Ci-6 alkanesulfonylamine) group, a carboxyl group, a C2-7 alkoxycarbonyl group, -con(rh)R1, and the following substituents (xvii) to (xxii) having 1 to 3 arbitrary groups selected from the following substituent group α as a ring substituent:

(xvii) Ce-i. Aryl, (xviii) Cs-i. Aryl-0-, (xix) C6-i. Fang (Cl-6 courtyard oxygen) base, (XX) C6-1. Aromatic (Cl-6 sulphur) group, (XXi) C3-7 cycloalkyl group or (xxii) C3-7 cycloalkyl group-0-; RB and R1 are each independently a hydrogen atom or may have 1 to 3 selected from Any of the following groups of substituents of Group 7 Cl-6 leuco; [Substituent group r] dentate atom 'transamination, amine group, C1-6 alkoxy group, halogenated (C1-6 oxy) group '(Cl-6), amine (Cl-6), mono or di(Cl-6) amino, mono or bis[hydroxy(1-6))], Urea, sulfonamide, mono or bis(0-6 alkyl)urea, mono or bis[hydroxy(Ci-6)]ureido, mono or di(Ci-6 alkane)sulfonamide, single Or bis[hydroxy(Ci-6 alkane)]sulfonamide, C2-7 mercaptoamine, amine (C2-7 hexylamine), Cl-6, and Cl-6 Amino group, amine ketone (Cl-6 alkanesulfonylamine) group, carboxyl group, C2-7 alkoxycarbonyl group, amidoxime group and -C0N(R:) RK; [Substituent group 5] halogen atom, Hydroxyl, amine, Ci-6 alkyl, Cm alkoxy, dentate (Ch 106 94106583

1351400 alkyl, functional (Ci-6 alkoxy), hydroxy (1-6 alkyl), C 2-7 alkoxycarbonyl), (〇1-6 oxy), amine ((} 1-6) base, amine (0丨-6 alkoxy mono or di(0-6 alkane) amine group, mono or bis[hydroxy(Ci-6 alkane)] group, Ci-6 broth, Cl- 6 brilliant amino-based, Cl-6 burning aryl amine (Cl-6) base, C2-7 alkoxycarbonyl, amine sulfonyl and -COIUR ^ R1; and R11 are each independently a hydrogen atom or It may have 1 to 3 substituents, an amine group, a mono or di(Ci-6 alkyl)amine group, a C2-7 alkoxycarbonyl group, and a Cl6 group of any of the amine groups. The condensed heterocyclic derivative of the above item 1, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein Q is an anthracenylene group, a group, -CH 2 - , -CH 2 〇- , - SCH 2 - or -CH 2 S- 3. A condensed heterocyclic derivative or a pharmaceutically acceptable salt thereof, or a prodrug thereof, as claimed in claim 2, wherein Q is an exoethyl group. a cyclic derivative or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein Q is an anthracene group. a condensed heterocyclic ring according to any one of the four items, or a pharmacologically acceptable salt thereof, or a prodrug thereof, wherein the ring (C 1 - 6 ) group, the continuation, and the carboxy group from the hydroxy hydrazine derivative

For ». A condensed hybrid according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, or a prodrug thereof, wherein 107 94106583 1351400

7. The condensed heterocyclic derivative of claim 1 or a pharmacologically acceptable salt thereof or a prodrug thereof, wherein R5 and R6 are each independently hydrogen

Atom, meridine, halogen atom, Cl-6 alkyl group, C2-6 cation group, C2-6 block group, Ci-6 decyloxy group, C2-6 C2-ealkenyloxy group, Ci-6 sulphur Base, C2-6 dilute sulfur group, ||chemical (Cl-6) group, halogenated (Cl-6 oxy-oxygen) group, functionalized (Cl-6 alkylthio) group, hydroxy (Ci-6 alkyl) group, Hydroxy (C2-s alkenyl)-hydroxy (Ci-6 alkoxy) group or hydroxy (C i-6 alkylthio) group. 8. The condensed heterocyclic derivative of claim 1 or a pharmacologically acceptable salt thereof or a prodrug thereof, wherein ring A is a stupid or acridine ring. 9. The condensed heterocyclic derivative of claim 5, or a pharmacologically acceptable salt thereof, or a prodrug thereof, wherein ring A is a benzene ring or. Than a pyridine ring. A condensed heterocyclic derivative or a pharmacologically acceptable salt thereof or a prodrug thereof, wherein the ring A is a benzene ring or a pharmaceutically acceptable salt thereof. Biidine ring. The condensed heterocyclic derivative or the pharmacologically acceptable salt thereof, or the prodrug, wherein the ring A is a benzene ring or a pharmaceutically acceptable salt thereof. Biidine ring. 12. The condensed heterocyclic derivative of any one of claims 1 to 4, 7, 8 and 11 or a pharmacologically acceptable salt thereof or a prodrug thereof, 108 94106583 1351400 wherein G is H〇"VY ho,, j^'〇h OH represents the base. A condensed heterocyclic derivative or a pharmacologically acceptable salt thereof, or a prodrug thereof, as claimed in claim 5, wherein G is

The base of expression. 1 4 . The condensed heterocyclic derivative of claim 6 or a pharmacologically acceptable salt thereof or a prodrug thereof, wherein G is

The base of expression. 15. The condensed heterocyclic derivative of claim 9 or a pharmacologically acceptable salt thereof or a prodrug thereof, wherein G is

The base of expression. 16. The condensed heterocyclic derivative of claim 10 or a pharmacologically acceptable salt thereof, or a precursor drug thereof, wherein G is 109 94106583 1351400

The base of expression. A pharmaceutical composition characterized by containing a condensed heterocyclic derivative of the first aspect of the patent application or a pharmacologically acceptable salt thereof or the prodrug as an active ingredient.

An inhibitor of human S G L T activity characterized by containing a fused heterocyclic derivative of the first aspect of the patent application or a pharmacologically acceptable salt thereof or such a prodrug as an active ingredient. 19. The human S G L T activity inhibitor according to claim 18, wherein the SGLT is SGLT1 and/or SGLT2. 2 〇 . For the human body S G L T activity inhibitor of claim 18, which is a postprandial hyperglycemic inhibitor. 2 1. A human S G L T activity inhibitor according to claim 18, which is a therapeutic agent for a disease caused by hyperglycemia. 2 2. The human SGLT activity inhibitor according to the scope of patent application No. 21, wherein the disease caused by hyperglycemia is selected from diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia Hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis, hypertension, septic heart disease, edema, hyperuricemia, and gout disease. 23. The human SGLT activity inhibitor according to claim 18, which is a metastasis inhibitor for preventing metastasis to diabetes. 110 94106583

1351400 2 4. A pharmaceutical composition according to claim 17 of the patent application, which is a preparation. 2 5. The human S G L T activity as claimed in claim 18 is a sustained release preparation. 26. The use of a condensed heterocyclic derivative or a scientologically acceptable salt of the first aspect of the patent application or the use of such a prodrug, which is characterized in that the pharmaceutical composition for suppressing hyperglycemia after cooking is used. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> . 28. The use of the scope of claim 27, wherein the disease caused by high blood is selected from diabetes, abnormal glucose tolerance, glycolytic complications, obesity, hypertonic acidemia, hyperlipidemia, high Bleeding, hypertriglyceridemia, abnormal fat metabolism, atherosclerosis, hypertension, stagnation of the heart, edema, hyperuricemia, and gout in the group. 2 9. A condensed heterocyclic derivative or a physiologically acceptable salt of the first application of the patent scope, or a use of the prodrug, which is characterized in that it is used for preventing metastasis of metastasis into diabetes caused by abnormal glucose tolerance Things. 94106583 A release agent, which is used in the manufacture of a drug for the treatment of diabetes, sedation, sterol hardening, and medicine.